Transdermal therapeutic system containing asenapine

ABSTRACT

The present invention relates to transdermal therapeutic systems (TTS) for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, such asenapine TTS for use in a method of treatment, processes of manufacture of such TTS as well as asenapine and transdermal therapeutic systems containing asenapine for use in a method of treatment and to a method of treating a human patient by transdermal administration of asenapine.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a transdermal therapeutic system (TTS)for the transdermal administration of asenapine to the systemiccirculation, and processes of manufacture, method of treatments and usesthereof.

BACKGROUND OF THE INVENTION

The active agent asenapine(3aRS,12bRS)-rel-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole)is an atypical antipsychotic belonging to the dibenzo-oxepino pyrrolefamily, the tetracyclic structure of which is unrelated to those ofother antipsychotics such as Olanzapine, Quetiapine or Clozapine(tricyclic structure), Risperidone, Ziprasidone or Aripiprazole(bicyclic structure). Asenapine is an antagonist at the dopamine D2 andserotonin 5-HT2A receptors with high affinity to the latter and has beendeveloped by Schering-Plough/Organon for the treatment of schizophreniaand acute mania associated with bipolar disorder.

Currently, asenapine is commercially available in the form of sublingualtablets, which is administered in dosage strengths of 2.5 mg, 5 mg or 10mg twice daily (BID) under the brand names Sycrest (Swissmedic) andSaphris (Schering-Plough).

The sublingual administration route avoids the first-pass metabolism ofan oral administration in order to increase bioavailability, which is at35% when taken sublingually and <2% if ingested. However, sublingualadministration is associated with bitter or unpleasant taste as well astongue/oral mucosal numbness induced by a local anesthetic effect,nausea and headaches. Further, eating, drinking and smoking are notallowed immediately after sublingual dosing for 10 min. Theseinconveniences may lead to reduced patient compliance and improperadministration such as dose reduction, dose skipping, irregular drugintake or a complete abstinence from the intended asenapine intake.Sublingual administration is also difficult to monitor ininstitutionalized psychiatric patients and may not be suitable forchildren, elderly and other patients with difficulty in swallowing, orfor those not capable of taking medication on their own.

Asenapine shows side effects which are not unusual for a neurolepticdrug. Somnolence and anxiety are very common (observed in ≥10% of thepatients). Other common (≥1% to <10% of the patients) adverse effectsinclude weight gain and increased appetite, nervous system disorderssuch as dystonia, akathisia, dyskinesia, parkinsonism, sedation,dizziness, dysgeusia; gastrointestinal disorders such as oralhypoesthesia, nausea, increased salivation; increases in alanineaminotransferase (ALT), muscle rigidity, and fatigue (tiredness).

Asenapine is metabolized hepatically, mainly via CYP1A2 and UGT1A4(glucuronidation). The clinical relevance of the main human metabolitesN-desmethyl-asenapine and asenapine N+ glucuronide remain controversial.It at least appears that the metabolites would not substantiallyparticipate in the therapeutic effect. Thus, a decrease in the amount ofthese metabolites appears generally desirable.

Following sublingual administration, asenapine is rapidly absorbed withpeak blood plasma concentrations occurring within 0.5 to 1.5 hours and(in therapeutic doses) exhibits 2-compartment pharmacokinetics with arapid initial distribution phase with a half-life of several hours,followed by a longer terminal disposition half-life of around 1 day orlonger. The blood plasma concentration thus exhibits a certain degree offluctuation with peaks about 1 h post-dose, followed by a concentrationdecrease resulting in a low point just before the next dose, even insteady state. The relatively rapid concentration decrease alsoinevitably leads to multiple daily doses (currently twice daily), whichare associated with poor patient compliance, in particular in chronicconditions.

Such fluctuation could be avoided, or at least reduced by transdermaladministration of asenapine, which prevents plasma concentrationdecrease between two doses to some extent by providing an extendedrelease of the active. Transdermal delivery of asenapine has beeninvestigated, but it appears that passive transdermal delivery ofasenapine, and in particular a constant release over an extended periodof time, is challenging. Passive transport of active agents from atransdermal therapeutic system (TTS) through the skin makes use of thedriving force based on the concentration gradient between theconcentration of active agent in the transdermal system and on the outersurface of the skin and the concentration in the blood stream. Suchpassive transport is advantageous in view of complexity of the TTS andthe convenience of administration compared to TTS making use of activetransportation such as iontophoresis or microporation. Up to date, nocommercial asenapine TTS is available.

There is thus a need in the art for a transdermal therapeutic system forthe transdermal administration of asenapine.

There is also a need for an appropriate administration of asenapine thatleads to less or less severe side effects.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a TTS overcoming theabove-mentioned disadvantages of current asenapine administration.

Thus, it is an object of the present invention to provide a TTS, and inparticular a matrix-type TTS, for the transdermal administration ofasenapine providing a permeation rate which is sufficient for achievinga therapeutically effective dose.

It is a further object of the present invention to provide a TTS, and inparticular a matrix-type TTS, for the transdermal administration ofasenapine in a continuous administration, providing therapeuticallyeffective amounts of asenapine for up to 7 days, during anadministration period to the skin of the patient of up to 7 days (e.g.3.5 days).

It is also an object of the present invention to provide a TS, and inparticular a matrix-type TTS, for the transdermal administration ofasenapine, wherein the fluctuation in asenapine blood plasmaconcentration is reduced when compared to sublingual administration, inparticular in steady state.

It is another object of the present invention to provide a TTS, and inparticular a matrix-type TTS, for the transdermal administration ofasenapine which complies with the needs of a convenient application inview of size and thickness and/or which is easy and cost-efficient tomanufacture.

It is an object of certain embodiments of the present invention toprovide a TTS, and in particular a matrix-type TTS, for the transdermaladministration of asenapine with an improved bioavailability ofasenapine.

It is an object of certain embodiments of the present invention toprovide a TTS, and in particular a matrix-type TTS, for the transdermaladministration of asenapine, wherein therapeutically effective amountsof asenapine are provided for 1 day by said transdermal therapeuticsystem during an administration period to the skin of the patient of 1day, allowing a once a day exchange of the TTS in an around the clocktreatment.

It is an object of certain embodiments of the present invention toprovide a TTS, and in particular a matrix-type TTS, for the transdermaladministration of asenapine, wherein therapeutically effective amountsof asenapine are provided for 3.5 days by said transdermal therapeuticsystem during an administration period to the skin of the patient of 3.5days, allowing a twice a week exchange of the TTS in an around the clocktreatment.

These objects and others are accomplished by the present invention,which according to one aspect relates to a transdermal therapeuticsystem for the transdermal administration of asenapine comprising aself-adhesive layer structure containing a therapeutically effectiveamount of asenapine, said self-adhesive layer structure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        1. asenapine; and        2. a polymer selected from acrylic polymers;        wherein the transdermal therapeutic system has an area of        release of from 5 to 100 cm².

According to a second aspect, the present invention relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containingasenapine, wherein the transdermal therapeutic system provides bytransdermal delivery a mean release rate of 0.5 to 20 mg/day over atleast 48 hours of administration.

According to a third aspect, the present invention relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containingasenapine, wherein the transdermal therapeutic system provides bytransdermal delivery an AUC₀₋₄₈ from 20 to 300 (ng/ml) h or from morethan 300 to 450 (ng/ml) h, preferably from 30 to 200 (ng/ml) h.

According to a fourth aspect, the present invention relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containingasenapine, wherein the transdermal therapeutic system provides bytransdermal delivery an AUC₀₋₇₂ from 30 to 400 (ng/ml) h or from morethan 400 to 600 (ng/ml) h, preferably from 50 to 300 (ng/ml) h.

According to a fifth aspect, the present invention relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containingasenapine, wherein the transdermal therapeutic system provides bytransdermal delivery an AUC₀₋₈₄ from 35 to 450 (ng/ml) h or from morethan 450 to 700 (ng/ml) h, preferably from 60 to 350 (ng/ml) h.

According to a sixth aspect, the present invention relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containingasenapine, wherein the transdermal therapeutic system provides bytransdermal delivery a C_(max) to C₄₈ ratio of less than 2.0, preferablyof less than 1.5 and more preferably of less than 1.3.

According to a seventh aspect, the present invention relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containingasenapine, wherein the transdermal therapeutic system provides bytransdermal delivery a C_(max) to C₇₂ ratio of less than 3.0, preferablyof less than 2.5 and more preferably of less than 2.0.

According to an eighth aspect, the present invention relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containingasenapine, wherein the transdermal therapeutic system provides bytransdermal delivery a C_(max) to C₈₄ ratio of less than 3.5, preferablyof less than 3.0, more preferably of less than 2.5 and most preferablyof less than 2.0.

According to a ninth aspect, the present invention relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containing atherapeutically effective amount of asenapine, said self-adhesive layerstructure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine in the form of the free base; and        -   2. a polymer;            wherein the area weight of the matrix layer is at least 90            g/m², and            wherein the asenapine-containing matrix layer does not            comprise isopropyl palmitate.

According to certain embodiments of the invention, the transdermaltherapeutic system according to the invention is for use in a method oftreatment, in particular for use in a method of treating schizophreniaand/or bipolar disorder, in particular during administration for anextended period of time.

Thus, according to certain embodiments of the invention, the transdermaltherapeutic system according to the invention is for use in a method oftreating schizophrenia and/or bipolar disorder during an administrationperiod of about 24 h to about 168 h, or 1 to 7 days, and in particularfor use in a method of treating schizophrenia and/or bipolar disorderduring an administration period of about 24 h, or 1 day, of about 48hours, or 2 days, or of about 84 h, or 3.5 days.

According to certain other embodiments of the invention, the transdermaltherapeutic system according to the invention is for use in a method oftreating psychosis in general, and in particular for use in a method oftreating one or more conditions selected from schizophrenia, bipolardisorder, posttraumatic stress disorder, major depressive disorder,dementia related psychosis, agitation and manic disorder, in particularduring administration for an extended period of time, e.g. during anadministration period of about 24 h to about 168 h, or 1 to 7 days, andin particular during an administration period of about 24 h, or 1 day,of about 48 hours, or 2 days, or of about 84 h, or 3.5 days.

According to other embodiments, the present invention relates to amethod of treatment, in particular to a method of treating schizophreniaand/or bipolar disorder, including applying a transdermal therapeuticsystem according to the invention to the skin of a patient for anextended period of time.

Thus, according to certain other embodiments, the invention relates to amethod of treating schizophrenia and/or bipolar disorder includingapplying a transdermal therapeutic system according to the invention forabout 24 h to about 168 h or for 1 to 7 days, or for about 24 h, 48 h or84 h, or for 1 day, 2 days or 3.5 days to the skin of a patient.

Such modes of administration require a once a day, once each two days,twice a week or a once a week exchange of the TTS in an around-the-clocktreatment.

According to certain other embodiments of the invention, the presentinvention relates to a method of treating psychosis in general, and inparticular to a method of treating one or more conditions selected fromschizophrenia, bipolar disorder, posttraumatic stress disorder, majordepressive disorder, dementia related psychosis, agitation and manicdisorder, in particular during administration for an extended period oftime, e.g. during an administration period of about 24 h to about 168 h,or 1 to 7 days, and in particular during an administration period ofabout 24 h, or 1 day, of about 48 hours, or 2 days, or of about 84 h, or3.5 days.

According to a specific aspect, the present invention relates toasenapine for use in a method of treating a human patient by transdermaladministration of asenapine for a dosing interval of at least about 48hours or 2 days, or of at least about 72 hours or 3 days.

According to a further specific aspect, the present invention relates toa transdermal therapeutic system for the transdermal administration ofasenapine for use in a method of treating a human patient for a dosinginterval of at least about 48 hours or 2 days, or of at least about 72hours or 3 days.

According to another specific aspect, the present invention relates to amethod of treating a human patient by transdermal administration ofasenapine for a dosing interval of at least about 48 hours or 2 days, orof at least about 72 hours or 3 days.

According to yet another specific aspect, the invention relates to aprocess of manufacture of a matrix layer for use in a transdermaltherapeutic system comprising the steps of:

-   -   1) combining at least the components asenapine and polymer, in a        solvent to obtain a coating composition;    -   2) coating the coating composition onto the backing layer or        release liner or any intermediate liner; and    -   3) drying the coated coating composition to form the matrix        layer.

According to certain embodiments the invention also relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate; and        -   3. a stabilizer.

According to certain embodiments the invention also relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of 3% to 9% of the matrix layer composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 90 to 96.5% of            the matrix layer composition; and        -   3. a stabilizer in an amount of from 0.1% to 2% of the            matrix layer composition:            wherein the area weight of the matrix layer ranges from 120            to 170 g/m².

According to certain embodiments the invention also relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate;        -   3. a stabilizer; and        -   4. a polyvinyl pyrrolidone.

According to certain embodiments the invention also relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of 3% to 9% of the matrix layer composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 80 to 90% of the            matrix layer composition;        -   3. a stabilizer in an amount of from 0.1% to 2% of the            matrix layer composition; and        -   4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of            the matrix layer composition.            wherein the area weight of the matrix layer ranges from 120            to 170 g/m².

According to certain embodiments the invention also relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of 7% to 13% of the matrix layer composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 75 to 85% of the            matrix layer composition;        -   3. a stabilizer in an amount of from 0.1% to 2% of the            matrix layer composition; and        -   4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of            the matrix layer composition.            wherein the area weight of the matrix layer ranges from 120            to 170 g/m².

According to certain embodiments the invention also relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of from more than 13% to 20% of the matrix layer            composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 65 to 82% of the            matrix layer composition;        -   3. a stabilizer in an amount of from 0.001% to 2% of the            matrix layer composition; and        -   4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of            the matrix layer composition.            wherein the area weight of the matrix layer ranges from 120            to 230 g/m².

According to certain embodiments the invention also relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of 7% to 20% of the matrix layer composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 75 to 85% of the            matrix layer composition;        -   3. a stabilizer in an amount of from 0.001% to 2% of the            matrix layer composition; and        -   4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of            the matrix layer composition.            wherein the area weight of the matrix layer ranges from more            than 170 to 230 g/m².

Within the meaning of this invention, the term “transdermal therapeuticsystem” (TTS) refers to a system by which the active agent (asenapine)is administered to the systemic circulation via transdermal delivery andrefers to the entire individual dosing unit that is applied to the skinof a patient, and which comprises a therapeutically effective amount ofasenapine in a self-adhesive layer structure and optionally anadditional adhesive overlay on top of the asenapine-containingself-adhesive layer structure. The self-adhesive layer structure may belocated on a release liner (a detachable protective layer), thus, theTTS may further comprise a release liner. Within the meaning of thisinvention, the term “TTS” in particular refers to a system providingpassive transdermal delivery excluding active transport as in methodsincluding iontophoresis or microporation.

Within the meaning of this invention, the term “asenapine-containingself-adhesive layer structure” or “self-adhesive layer structurecontaining a therapeutically effective amount of asenapine” refers tothe active agent-containing structure providing the area of release forasenapine during administration. The adhesive overlay adds to theoverall size of the TTS but does not add to the area of release. Theasenapine-containing self-adhesive layer structure comprises a backinglayer and at least one asenapine-containing layer.

Within the meaning of this invention, the term “therapeuticallyeffective amount” refers to a quantity of active agent in the TTSsufficient to provide, if administered by the TTS to a patient,asenapine blood levels of a similar range (e.g. of about 10% to about1000% as measured as an AUC) when compared to blood levels obtained insteady state administration of twice daily 5 mg sublingual asenapineover a predefined extended period of time (e.g. 1, 3.5 and 7 days). ATTS usually contains more active in the system than is in fact providedto the skin and the systemic circulation. This excess amount of activeagent is usually necessary to provide enough driving force for thepassive transportation from the TTS to the systemic circulation.

Within the meaning of this invention, the terms “active”. “activeagent”, and the like, as well as the term “asenapine” refer to asenapinein any pharmaceutically acceptable chemical and morphological form andphysical state. These forms include without limitation asenapine in itsfree base form, protonated or partially protonated asenapine, asenapinesalts and in particular acid addition salts formed by addition of aninorganic or organic acid such as asenapine hydrochloride or asenapinemaleate, hydrates, complexes and so on, as well as asenapine in the formof particles which may be micronized, crystalline and/or amorphous, andany mixtures of the aforementioned forms. The asenapine, where containedin a medium such as a solvent, may be dissolved or dispersed or in partdissolved and in part dispersed.

When asenapine is mentioned to be used in a particular form in themanufacture of the TTS, this does not exclude interactions between thisform of asenapine and other ingredients of the asenapine-containingself-adhesive layer structure, e.g. salt formation or complexation, inthe final TTS. This means that, even if asenapine is included in itsfree base form, it may be present in the final TTS in protonated orpartially protonated form or in the form of an acid addition salt, or,if it is included in the form of a salt, parts of it may be present asfree base in the final TTS. Unless otherwise indicated, in particularthe amount of asenapine in the self-adhesive layer structure relates tothe amount of asenapine included in the TTS during manufacture of theITS and is calculated based on asenapine in the form of the free base.E.g., when a) 0.1 mmol (equal to 28.6 mg) asenapine base or b) 0.1 mmol(equal to 40.2 mg) asenapine maleate is included in the TTS duringmanufacture, the amount of asenapine in the self-adhesive layerstructure is, within the meaning of the invention, in both cases 0.1mmol or 28.6 mg.

The asenapine starting material included in the ITS during manufactureof the TTS may be in the form of particles. Asenapine may e.g. bepresent in the self-adhesive layer structure in the form of particlesand/or dissolved.

Within the meaning of this invention, the term “particles” refers to asolid, particulate material comprising individual particles, thedimensions of which are negligible compared to the material. Inparticular, the particles are solid, including plastic/deformablesolids, including amorphous and crystalline materials.

Within the meaning of this invention, the term “dispersing” refers to astep or a combination of steps wherein a starting material (e.g.asenapine) is not totally dissolved. Dispersing in the sense of theinvention comprises the dissolution of a part of the starting material(e.g. asenapine particles), depending on the solubility of the startingmaterial (e.g. the solubility of asenapine in the coating composition).

There are two main types of TTS using passive active agent delivery,i.e. matrix-type ITS and reservoir-type TTS. In matrix-type TTS theactive agent is included in a matrix, while in a reservoir-type TTS theactive agent is included in a liquid or semi-liquid reservoir. Therelease of the active agent in a matrix-type TTS is mainly controlled bythe matrix including the active agent itself. In contrast thereto, areservoir-type TTS needs a rate-controlling membrane controlling therelease of the active agent. Matrix-type TTS are advantageous in that,compared to reservoir type TTS, usually no rate determining membranesare necessary and no dose dumping can occur due to membrane rupture. Insummary, matrix-type transdermal therapeutic systems (TTS) are lesscomplex in manufacture and easy and convenient to use by patients.

Within the meaning of this invention. “matrix-type TTS” refers to asystem or structure wherein the active is homogeneously dissolved and/ordispersed within a polymeric carrier, i.e. the matrix, which forms withthe active agent and optionally remaining ingredients a matrix layer. Insuch a system, the matrix layer controls the release of the active agentfrom the TTS. A matrix-type TTS may also include a rate-controllingmembrane.

TTS with a rate-controlling membrane and a liquid or semi-liquid activeagent containing reservoir, wherein the release of the active agent fromthe TTS is controlled by the rate-controlling membrane, are referred toby the term “reservoir-type ITS”. Reservoir-type TTS are not to beunderstood as being of matrix-type within the meaning of the invention.In particular, within the meaning of this invention,microreservoir-systems (biphasic systems having an inneractive-containing phase in an outer matrix-phase), considered in the artto be a mixture between a matrix-type TTS and a reservoir-type TTS, areconsidered to be of matrix-type within the meaning of the invention.Matrix-type TTS may in particular be in the form of a“drug-in-adhesive”-type UTS referring to a system wherein the active ishomogeneously dissolved and/or dispersed within a pressure-sensitiveadhesive matrix.

Within the meaning of this invention, the term “matrix layer” refers toany layer containing the active homogeneously dissolved and/or dispersedwithin a polymeric carrier. Typically, a matrix layer is present in amatrix-type TTS as the active agent-containing layer. A reservoir-typeTTS may comprise, in addition to a reservoir layer and arate-controlling membrane, an additional adhesive layer which serves asa skin contact layer. In such a reservoir-type TTS, the additionaladhesive layer often is manufactured as an active agent-free layer.However, due to the concentration gradient, the active agent willmigrate from the reservoir to the additional adhesive layer over time,until an equilibrium is reached. Therefore, in such a reservoir-typeTTS, after some time of equilibration, the additional adhesive layercontains the active agent and is to be regarded as a matrix layer in thesense of the present invention.

The matrix layer is the final, solidified layer e.g. obtained aftercoating and drying the solvent-containing coating composition. Thematrix layer may also be manufactured by laminating two or more suchsolidified layers (e.g. dried layers) of the same composition to providethe desired area weight. The matrix layer may be self-adhesive (in theform of a pressure sensitive adhesive matrix) or the TTS may comprise anadditional skin contact layer of a pressure sensitive adhesive forproviding sufficient tack. In particular, the matrix layer is a pressuresensitive adhesive matrix.

Within the meaning of this invention, the term “pressure-sensitiveadhesive” refers to a material that in particular adheres with fingerpressure, is permanently tacky, exerts a strong holding force and shouldbe removable from smooth surfaces without leaving a residue. A pressuresensitive adhesive layer, when in contact with the skin, is“self-adhesive”, i.e. provides adhesion to the skin so that typically nofurther aid for fixation on the skin is needed. A “self-adhesive” layerstructure includes a pressure sensitive adhesive layer for skin contactwhich may be provided in the form of a pressure sensitive adhesivematrix or in the form of an additional layer, i.e. a pressure sensitiveadhesive skin contact layer. An adhesive overlay may still be employedto advance adhesion.

Within the meaning of this invention, the term “skin contact layer”refers to a layer included in the TTS to be in direct contact with theskin of the patient during administration. When the TTS comprises a skincontact layer, the other layers do not contact the skin and do notnecessarily have self-adhesive properties. As outlined above, the skincontact layer may over time absorb parts of the active agent and thenmay be regarded as a matrix layer. The area of release is provided bythe area of the matrix layer. A skin contact layer may be used toenhance adherence. The sizes of an additional skin contact layer and thematrix layer are usually coextensive and correspond to the area ofrelease.

Within the meaning of this invention, the term “area weight” refers tothe dry weight of a specific layer, e.g. of the matrix layer, providedin g/m². The area weight values are subject to a tolerance of +10%,preferably ±7.5%, due to manufacturing variability.

If not indicated otherwise “%” refers to weight-%.

Within the meaning of this invention, the term “polymer” refers to anysubstance consisting of so-called repeating units obtained bypolymerizing one or more monomers, and includes homopolymers whichconsist of one type of monomer and copolymers which consist of two ormore types of monomers. Polymers may be of any architecture such aslinear polymers, star polymer, comb polymers, brush polymers, of anymonomer arrangements in case of copolymers, e.g. alternating,statistical, block copolymers, or graft polymers. The minimum molecularweight varies depending on the polymer type and is known to the skilledperson. Polymers may e.g. have a molecular weight above 2,000,preferably above 5,000 and more preferably above 10,000 Dalton.Correspondingly, compounds with a molecular weight below 2,000,preferably below 5,000 or more preferably below 10,000 Dalton areusually referred to as oligomers.

Within the meaning of this invention, the term “functional groups”refers to hydroxy- and carboxylic acid groups.

Within the meaning of this invention, the term “cross-linking agent”refers to a substance which is able to cross-link functional groupscontained within the polymer.

Within the meaning of this invention, the term “adhesive overlay” refersto a self-adhesive layer structure that is free of active agent andlarger in area than the active agent-containing structure and providesadditional area adhering to the skin, but no area of release of theactive agent. It enhances thereby the overall adhesive properties of theTTS. The adhesive overlay comprises a backing layer and an adhesivelayer.

Within the meaning of this invention, the term “backing layer” refers toa layer, which supports e.g. the asenapine-containing layer or forms thebacking of the adhesive overlay. At least one backing layer in the TTSand usually the backing layer of the asenapine-containing layer isocclusive, i.e. substantially impermeable to the active agent containedin the layer during the period of storage and administration and thusprevents active loss or cross-contamination in accordance withregulatory requirements.

The TTS according to the present invention can be characterized bycertain parameters as measured in an in vitro skin permeation test.

The in vitro permeation test is performed in a Franz diffusion cell,with human or animal skin and preferably with dermatomed split-thicknesshuman skin with a thickness of 800 μm and an intact epidermis, and withphosphate buffer pH 5.5 or 7.4 as receptor medium (32° C. with 0.1%saline azide) with or without addition of a maximum of 40 vol-% organicsolvent e.g. ethanol, acetonitrile, isopropanol, dipropylenglycol, PEG400 so that a receptor medium may e.g. contain 60 vol-% phosphate bufferpH 5.5, 30 vol-% dipropylenglycol and 10 vol-% acetonitrile.

Where not otherwise indicated, the in vitro permeation test is performedwith dermatomed split-thickness human skin with a thickness of 800 μmand an intact epidermis, and with phosphate buffer pH 5.5 as receptormedium (32° C. with 0.1% saline azide). The amount of active permeatedinto the receptor medium is determined in regular intervals using avalidated HPLC method with a UV photometric detector by taking a samplevolume. The receptor medium is completely or in part replaced by freshmedium when taking the sample volume, and the measured amount of activepermeated relates to the amount permeated between the two last samplingpoints and not the total amount permeated so far.

Thus, within the meaning of this invention, the parameter “permeatedamount” is provided in pig/cm² and relates to the amount of activepermeated in a sample interval at certain elapsed time. E.g., in an invitro permeation test as described above, wherein the amount of activepermeated into the receptor medium has been e.g. measured at hours 0, 2,4, 8, 12 and 24, the “permeated amount” of active can be given e.g. forthe sample interval from hour 8 to hour 12 and corresponds to themeasurement at hour 12.

The permeated amount can also be given as a “cumulative permeatedamount”, corresponding to the cumulated amount of active permeated at acertain point in time. E.g., in an in vitro permeation test as describedabove, wherein the amount of active permeated into the receptor mediumhas been e.g. measured at hours 0, 2, 4, 8, 12 and 24, the “cumulativepermeated amount” of active at hour 12 corresponds to the sum of thepermeated amounts from hour 0 to hour 2, hour 2 to hour 4, hour 4 tohour 8 and hour 8 to hour 12.

Within the meaning of this invention, the parameter “skin permeationrate” for a certain sample interval at certain elapsed time is providedin μg/(cm² h) and is calculated from the permeated amount in said sampleinterval as measured by in vitro permeation test as described above inμg/cm², divided by the hours of said sample interval. E.g. the skinpermeation rate in an in vitro permeation test as described above,wherein the amount of active permeated into the receptor medium has beene.g. measured at hours 0, 2, 4, 8, 12 and 24, the “skin permeation rate”at hour 12 is calculated as the permeated amount in the sample intervalfrom hour 8 to hour 12 divided by 4 hours.

A “cumulative skin permeation rate” can be calculated from therespective cumulative permeated amount by dividing the cumulativepermeated amount by the elapsed time. E.g. in an in vitro permeationtest as described above, wherein the amount of active permeated into thereceptor medium has been e.g. measured at hours 0, 2, 4, 8, 12 and 24,the “cumulative skin permeation rate” at hour 12 is calculated as thecumulative permeated amount for hour 12 (see above) divided by 12 hours.

Within the meaning of this invention, the above parameters permeatedamount and skin permeation rate (as well as cumulative permeated amountand cumulative skin permeation rate) refer to mean values calculatedfrom 3 in vitro permeation test experiments.

The TTS according to the present invention can also be characterized bycertain parameters as measured in an in vive clinical study.

Within the meaning of this invention, the parameter “mean release rate”refers to the mean release rate in μg/h, in mg/h, in μg/24 h, in mg/24h, in μg/day or in mg/day over the period of administration (e.g. 1 to 7day(s)) by which the active agent is released through the human skininto the systemic circulation and is based on the AUC obtained over saidperiod of administration in a clinical study. The mean release rate is aparameter used to identify the dose or the strength of a TTS. Since, incontrast to e.g. intravenous or oral administration and (as alsodescribed above) a TTS usually contains more active in the system thanis in fact provided to the skin and the systemic circulation, the amountof active contained in the TTS is not meaningful as a parameter for thedose. This is why for a TTS the dose or strength is usuallycharacterized by the mean release rate, which describes more accuratelythe amount of active delivered to the subject over time.

Within the meaning of this invention, the term “extended period of time”relates to a period of at least or about 24 h. at least or about 48 h,at least or about 84 h, at least or about 168 h, at least or about 1day, at least or about 3.5 days, or at least or about 7 days, or to aperiod of about 24 h to about 168 h or 1 to 7 day(s), or about 24 h toabout 84 h or 1 to 3.5 day(s).

For a continuous drug treatment, the frequency of drug administration ispreferably kept sufficiently high so as to maintain a therapeuticallyeffective blood plasma concentration. In other words, the intervalbetween two dosage form administrations, also called dosing interval,needs to be adapted accordingly. Within the meaning of the presentinvention, the term “dosing interval” refers to the period of timebetween two consecutive TTS administrations, i.e. the interval betweentwo consecutive points in time a ITS is applied to the skin of thepatient. Once applied, the TTS is usually maintained on the skin of thepatient for the entire dosing interval and only removed at the end ofthe dosing interval, at which time a new TTS is applied to the skin.E.g., if the dosing interval is 168 hours or 7 days, the TTS is appliedto and maintained on the skin of the patient for 168 hours or 7 days.After 168 hours or 7 days, the TTS is removed from the skin and a newTTS is applied. Thus, a dosing interval of 168 hours or 7 days allows aonce-a-week TTS exchange mode in an around-the-clock treatment.

Within the meaning of this invention, the term “room temperature” refersto the unmodified temperature found indoors in the laboratory where theexperiments are conducted and usually lies within 15 to 35° C.,preferably about 18 to 25° C.

Within the meaning of this invention, the term “patient” refers to asubject who has presented a clinical manifestation of a particularsymptom or symptoms suggesting the need for treatment, who is treatedpreventatively or prophylactically for a condition, or who has beendiagnosted with a condition to be treated.

Within the meaning of this invention the term “pharmacokineticparameters” refers to parameters describing the blood plasma curve, e.g.C_(max), C_(t) and AUC_(t1-t2) obtained in a clinical study, e.g. bysingle-dose, multi-dose or steady state administration of the activeagent TTS, e.g. the asenapine TTS to healthy human subjects. Thepharmacokinetic parameters of the individual subjects are summarizedusing arithmetic and geometric means, e.g. a mean C_(max), a meanAUC_(t) and a mean AUC_(INF), and additional statistics such as therespective standard deviations and standard errors, the minimum value,the maximum value, and the middle value when the list of values isranked (Median). In the context of the present invention,pharmacokinetic parameters, e.g. the C_(max), C_(t) and AUC_(t1-t2)refer to arithmetic or geometric mean values and preferably refer togeometric mean values. It cannot be precluded that the absolute meanvalues obtained for a certain ITS in a clinical study vary to a certainextent from study to study. To allow a comparison of absolute meanvalues between studies, a reference formulation, e.g. in the future anyproduct based on the invention, may be used as internal standard. Acomparison of the AUC per area of release of the respective referenceproduct in the earlier and later study can be used to obtain acorrection factor to take into account differences from study to study.

Clinical studies according to the present invention refer to studiesperformed in full compliance with the International Conference forHarmonization of Clinical Trials (ICH) and all applicable local GoodClinical Practices (GCP) and regulations.

Within the meaning of this invention, the term “healthy human subject”refers to a male or female subject with a body weight ranging from 55 kgto 100 kg and a body mass index (BMI) ranging from 18 to 29 and normalphysiological parameters, such as blood pressure, etc. Healthy humansubjects for the purposes of the present invention are selectedaccording to inclusion and exclusion criteria which are based on and inaccordance with recommendations of the ICH.

Within the meaning of this invention, the term “subject population”refers to at least ten individual healthy human subjects.

Within the meaning of this invention, the term “geometric mean” refersto the mean of the log transformed data back-transformed to the originalscale.

Within the meaning of this invention, the term “arithmetic mean” refersto the sum of all values of observation divided by the total number ofobservations.

Within the meaning of this invention, the parameter “AUC” corresponds tothe area under the plasma concentration-time curve. The AUC value isproportional to the amount of active agent absorbed into the bloodcirculation in total and is hence a measure for the bioavailability.

Within the meaning of this invention, the parameter “AUC_(t1-t2)” isprovided in (ng/ml) h and relates to the area under the plasmaconcentration-time curve from hour t1 to t2 and is calculated by thelinear trapezoidal method.

Within the meaning of this invention, the parameter “C_(max)” isprovided in (ng/ml) and relates to the maximum observed blood plasmaconcentration of the active agent.

Within the meaning of this invention, the parameter “C_(t)” is providedin (ng/ml) and relates to the blood plasma concentration of the activeagent observed at hour t.

Within the meaning of this invention, the parameter “t_(max)” isprovided in h and relates to the time point at which the C_(max) valueis reached. In other words, t_(max) is the time point of the maximumobserved plasma concentration.

Within the meaning of this invention, the parameter “t_(max)” isprovided in h and relates to the delay between the time ofadministration (in case of a TTS the time when the TTS is first appliedto the skin, i.e. t=0) and the time of appearance of measurable bloodplasma concentration. The t_(lag) can be calculated approximatively asthe mean arithmetic value of the first point in time when a measurable(i.e. non-zero) active agent blood plasma concentration is obtained orrepresented by a median value.

Within the meaning of this invention, the term “mean plasmaconcentration” is provided in (ng/ml) and is a mean of the individualplasma concentrations of active agent, e.g. asenapine, at each point intime.

Within the meaning of this invention, the term “coating composition”refers to a composition comprising all components of the matrix layer ina solvent, which may be coated onto the backing layer or release linerto form the matrix layer upon drying.

Within the meaning of this invention, the term “dissolve” refers to theprocess of obtaining a solution, which is clear and does not contain anyparticles, as visible to the naked eye.

Within the meaning of this invention, the term “solvent” refers to anyliquid substance, which preferably is a volatile organic liquid such asmethanol, ethanol, isopropanol, acetone, ethyl acetate, methylenechloride, hexane, n-heptane, toluene and mixtures thereof.

Within the meaning of this invention, and unless otherwise specified,the term “about” refers to an amount that is +10% of the disclosedamount. In some embodiments, the term “about” refers to an amount thatis ±5% of the disclosed amount. In some embodiments, the term “about”refers to an amount that is ±2% of the disclosed amount.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 1a, 1b, 1c and 1d for hours 0 to 72.

FIG. 1b depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 1a, 1b, 1c and 1d for hours 0 to 168.

FIG. 1c depicts the utilisation of asenapine of TTS prepared accordingto Examples 1a, 1b, 1c and 1d after 72 h.

FIG. 2a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 2a, 2b, 2c and 2d for hours 0 to 72.

FIG. 2b depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 2a, 2b, 2c and 2d for hours 0 to 168.

FIG. 2c depicts the utilisation of asenapine of ITS prepared accordingto Examples 2a, 2b, 2c and 2d after 72 h.

FIG. 2d depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 2e to 2j for hours 0 to 72.

FIG. 2e depicts the utilisation of asenapine of TTS prepared accordingto Examples 2e to 2j after 72 h.

FIG. 3a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 3a, 3b, 3c, 3d and 3e.

FIG. 3b depicts the utilisation of asenapine of TTS prepared accordingto Examples 3a, 3b, 3c, 3d and 3e after 56 h.

FIG. 4a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 4a and 4b for hours 0 to 72.

FIG. 4b depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 4a and 4b for hours 0 to 168.

FIG. 4c depicts the utilisation of asenapine of ITS prepared accordingto Examples 4a and 4b after 72 h and 168 h.

FIG. 5a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 5a, 5b and 5c for hours 0 to 72.

FIG. 5b depicts the utilisation of asenapine of TTS prepared accordingto Examples 5a, 5b and 5c after 72 h.

FIG. 6a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 6a, 6b and 6c for hours 0 to 72.

FIG. 6b depicts the utilisation of asenapine of ITS prepared accordingto Examples 6a, 6b and 6c after 72 h.

FIG. 7a depicts the asenapine skin permeation rate of ITS preparedaccording to Examples 7a, 7b and 7c for hours 0 to 72.

FIG. 7b depicts the utilisation of asenapine of TTS prepared accordingto Examples 7a, 7b and 7c after 72 h.

FIG. 8a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 8a, 8b and 8c for hours 0 to 72.

FIG. 8b depicts the utilisation of asenapine of TTS prepared accordingto Examples 8a, 8b and 8c after 72 h.

FIG. 9a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 9a and 9b for hours 0 to 72.

FIG. 9b depicts the utilisation of asenapine of T'S prepared accordingto Examples 9a and 9b after 72 h.

FIG. 10a depicts the asenapine skin permeation rate of TTS preparedaccording to Example 10 for hours 0 to 72.

FIG. 10b depicts the utilisation of asenapine of TTS prepared accordingto Example 10 after 72 h.

FIG. 11 depicts the asenapine blood plasma concentration of TTS preparedaccording to Examples 11a, 11b, 11c and 11d.

FIG. 12a depicts the asenapine skin permeation rate of ITS preparedaccording to Examples 12a and 12b for hours 0 to 72.

FIG. 12b depicts the utilisation of asenapine of TTS prepared accordingto Examples 12a and 12b after 72 h.

FIG. 13a depicts the asenapine blood plasma concentration (arithmeticmean values with standard deviation as error bars) obtained in an invivo clinical study of the TTS prepared according to Examples 13a and13b for hours 0 to 168.

FIG. 13b depicts the asenapine blood plasma concentration (arithmeticmean values with standard deviation as error bars) obtained in an invivo clinical study of the TTS prepared according to Examples 13a and13b for hours 0 to 84.

FIG. 13c depicts the asenapine-glucuronide blood plasma concentration(geometric mean values with geometric mean multiplied with/divided bythe geometric standard deviation as error bars) obtained in an in vivoclinical study of the TTS prepared according to Examples 13a and 13b forhours 0 to 168.

FIG. 13d depicts the asenapine-glucuronide blood plasma concentration(geometric mean values with geometric mean multiplied with/divided bythe geometric standard deviation as error bars) obtained in an in vivoclinical study of the TIS prepared according to Examples 13a and 13b forhours 0 to 96.

FIG. 13e depicts the N-desmethyl-asenapine blood plasma concentration(geometric mean values with geometric mean multiplied with/divided bythe geometric standard deviation as error bars) obtained in an in vivoclinical study of the TTS prepared according to Examples 13a and 13b forhours 0 to 108.

DETAILED DESCRIPTION TTS Structure

The present invention is related to a transdermal therapeutic system forthe transdermal administration of asenapine comprising a self-adhesivelayer structure containing asenapine.

In particular, the self-adhesive layer structure may comprisetherapeutically effective amounts of asenapine.

Preferably, the self-adhesive layer structure according to the presentinvention comprises A) a backing layer, and B) an asenapine-containingmatrix layer consisting of a matrix layer composition comprising 1.asenapine and 2. a polymer.

Thus, according to a certain embodiment of the invention, thetransdermal therapeutic system for the transdermal administration ofasenapine comprises a self-adhesive layer structure containing atherapeutically effective amount of asenapine, said self-adhesive layerstructure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine; and        -   2. a polymer selected from acrylic polymers;            wherein the transdermal therapeutic system has an area of            release of from 5 to 100 cm².

According to another certain embodiment of the invention the transdermaltherapeutic system for the transdermal administration of asenapinecomprises a self-adhesive layer structure containing a therapeuticallyeffective amount of asenapine, said self-adhesive layer structurecomprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine in the form of the free base; and        -   2. a polymer;            wherein the area weight of the matrix layer is at least 90            g/m², and wherein the asenapine-containing matrix layer does            not comprise isopropyl palmitate.

The backing layer is in particular substantially asenapine-impermeable.

The ITS according to the present invention may be a matrix-type ITS or areservoir-type TTS, and preferably is a matrix-type TTS.

In such a matrix-type TTS, the asenapine, and preferably atherapeutically effective amount of asenapine, is included in theasenapine-containing matrix layer. The self-adhesive layer structure insuch a matrix-type TTS can include one or more further layers such as askin contact layer. In such a further layer, the active agent may beincluded or may not be included. As outlined above, a skin contact layercan, even if manufactured as an active agent-free layer, afterequilibration, comprise asenapine and then may also be regarded as a(further) matrix layer. The further layer and the asenapine-containingmatrix layer may comprise the same polymer or different polymers. Any ofthe asenapine-containing matrix layer and the further layer(s) may bedirectly contacting each other or separated by a membrane such as a ratecontrolling membrane. If an asenapine-containing layer is prepared bylaminating two asenapine-containing matrix layers, which are ofsubstantially the same composition, the resulting double layer is to beregarded as one matrix layer.

In a reservoir-type TTS according to the present invention, theasenapine is included in a liquid or semi-liquid reservoir. Theself-adhesive layer structure in such a reservoir-type TTS can includeone or more further layers such as a skin contact layer. In such afurther layer, the active agent may be included or may not be included.As outlined above, a skin contact layer can, even if manufactured as anactive agent-free layer, after equilibration, comprise asenapine andthen may also be regarded as a matrix layer. The reservoir-type ITSfurther includes a rate controlling membrane separating the reservoirand skin contact layer.

Thus, in certain embodiments, the self-adhesive layer structurecomprises an additional reservoir layer which is located between thebacking layer and the matrix layer, and a further rate controllingmembrane which is located between the additional reservoir layer and thematrix layer.

In specific embodiments, the self-adhesive layer structure according tothe invention comprises an additional skin contact layer. The additionalskin contact layer is self-adhesive and provides for adhesion betweenthe self-adhesive layer structure and the skin of the patient duringadministration.

In such embodiments, the self-adhesive layer structure may or may notcomprise a membrane which is located between the matrix layer and theadditional skin contact layer, wherein the membrane is preferably a ratecontrolling membrane.

In another embodiment, the self-adhesive layer structure according tothe invention does not comprise an additional skin contact layer.Sufficient adhesion between the self-adhesive layer structure and theskin of the patient during administration is then provided for by othermeans, e.g. an asenapine-containing matrix layer and/or an adhesivelayer.

Thus, according to certain embodiments of the invention, the TTS mayfurther comprise an adhesive overlay or does not comprise an adhesiveoverlay, and preferably does not comprise an adhesive overlay. Thisadhesive overlay is in particular larger than the asenapine-containingself-adhesive layer structure and is attached thereto for enhancing theadhesive properties of the overall transdermal therapeutic system. Saidadhesive overlay comprises also a backing layer. The area of saidadhesive overlay adds to the overall size of the TTS but does not add tothe area of release. The adhesive overlay comprises a self-adhesivepolymer or a self-adhesive polymer mixture selected from the group ofacrylic polymers, polyisobutylenes, styrene-isoprene-styrene copolymers,polysiloxanes, and mixtures thereof, which may be identical to ordifferent from any polymer or polymer mixture included in the activeagent-containing self-adhesive layer structure.

The self-adhesive layer structure according to the invention is normallylocated on a detachable protective layer (release liner) from which itis removed immediately before application to the surface of thepatient's skin. Thus, the TTS may further comprise a release liner. ATTS protected this way is usually stored in a seam-sealed pouch. Thepackaging may be child resistant and/or senior friendly.

Matrix Layer and Matrix Layer Composition

As outlined in more detail above, the TTS according to certainembodiments of the present invention comprises a self-adhesive layerstructure comprising an asenapine-containing matrix layer consisting ofa matrix layer composition.

In these embodiments, the matrix layer composition comprises:

1. asenapine; and

2. a polymer;

In a specific embodiment of the invention, the matrix layer compositioncomprises asenapine and a polymer selected from acrylic polymers,wherein the transdermal therapeutic system has an area of release offrom 5 to 100 cm².

In certain embodiments of the invention, the area of release ranges from5 to 100 cm², preferably from 10 to 80 cm², and more preferably from 10to 25 cm² or from 10 to 20 cm², from 25 to 55 cm² or from 25 to 35 cm²or from 55 to 65 cm², i.e. the transdermal therapeutic system has anarea of release of from 5 to 100 cm², preferably from 10 to 80 cm², andmore preferably from 10 to 25 cm² or from 10 to 20 cm², from 25 to 55cm² or from 25 to 35 cm² or from 55 to 65 cm².

In another specific embodiment of the invention, the matrix layercomposition comprises asenapine in the form of the free base and apolymer, wherein the area weight of the matrix layer is at least 90 g/m²and wherein the asenapine-containing matrix layer does not compriseisopropyl palmitate.

In certain embodiments of the invention, the area weight of the matrixlayer ranges from 90 to 230 g/m², preferably from 110 to 210 g/m², andmost preferably from 120 to 170 g/m².

Without wishing to be bound by theory, it is believed that theadvantageous features of the TTS according to the present invention,such as good in vitro skin permeation are inter alia achieved by theamount of asenapine contained in the ITS, which can be controlledtwo-way by adjusting concentration and/or the area weight of theasenapine-containing layers such as the matrix layer.

Thus, in certain embodiments of the invention, the transdermaltherapeutic system contains at least 0.70 mg/cm², preferably at least0.80 mg-cm², more preferably at least 0.82 mg/cm² and most preferably atleast 0.83 mg/cm² asenapine per area of release. In certain furtherembodiments of the invention, the transdermal therapeutic systemcontains at least 0.90 mg/cm², at least 1.00 mg/cm², at least 1.2mg/cm², at least 1.5 mg/cm² or at least 2.0 mg/cm² asenapine per area ofrelease.

In particular, the transdermal therapeutic system contains from 0.70mg/cm² to 4.0 mg/cm², preferably from 0.80 mg/cm² to 3.0 mg/cm², morepreferably from 0.82 mg/cm² to 2.0 mg/cm² and most preferably from 0.83mg/cm² to 1.7 mg/cm² asenapine.

In certain embodiments of the invention, the matrix layer composition isa pressure-sensitive adhesive composition. The matrix layer compositionmay comprise a second polymer or may comprise two or more furtherpolymers.

According to certain embodiments of the invention, the total polymercontent in the matrix layer composition ranges from 75 to 97%,preferably from 80 to 96% and more preferably from 85 to 95% of thematrix layer composition. In any event does the matrix layer includesufficient amounts of polymer to provide sufficient cohesion.

According to certain embodiments, the amount of asenapine contained inthe TTS, in particular in the matrix layer of the TTS, ranges from 5 to100 mg, preferably from 10 to 80 mg, and most preferably from 15 to 60mg.

In certain embodiments, the transdermal therapeutic system has an areaof release of from 5 to 100 cm², and the amount of asenapine containedin the TTS ranges from 5 to 100 mg.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise isopropyl palmitate in an amount of 10% of thematrix layer composition, preferably does not comprise isopropylpalmitate in an amount of 5-15% of the matrix layer composition and mostpreferably does not comprise isopropyl palmitate.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise isopropyl myristate in an amount of 5% of thematrix layer composition, preferably does not comprise isopropylmyristate in an amount of 1-10% of the matrix layer composition and mostpreferably does not comprise isopropyl myristate.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise ethyl cellulose in an amount of 10-20% of thematrix layer composition and preferably does not comprise ethylcellulose.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise hydrogen chloride.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise sodium acetate or sodium diacetate. In yetanother embodiment, the asenapine-containing layer does not comprise adicarboxylic acid alkali salt. In yet another embodiment, theasenapine-containing layer does not comprise a maleic acid alkali salt.

In certain embodiments of the invention, the matrix layer compositiondoes not comprise any of polysiloxanes and polyisobutylenes in an amountof more than 50% of the matrix layer composition.

In certain embodiments, the asenapine-containing matrix layer isobtainable by drying a coated coating composition wherein nohydrochloric acid has been included in the coating composition.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise toluene.

In certain embodiments of the invention, the asenapine-containing matrixlayer is obtainable by drying a coated coating composition comprising notoluene.

Asenapine

In accordance with the invention, the self-adhesive layer structurecontains asenapine, in particular in a therapeutically effective amount.

In certain embodiments, the self-adhesive layer structure comprises anasenapine-containing matrix layer consisting of a matrix layercomposition comprising asenapine.

While in accordance with the present invention, the active agent may bepresent in the TTS in protonated or in free base form, the free baseform is preferred.

Thus, in certain embodiments, the asenapine in the matrix layercomposition is included in the form of the free base.

In certain embodiments, the matrix layer composition is obtainable byincorporating the asenapine in the form of the free base.

In particular, at least 90 mol %, preferably at least 95 mol %, morepreferably at least 98 mol % and most preferably at least 99 mol % ofthe asenapine in the matrix layer is present in the form of the freebase.

The asenapine in the matrix layer may be completely dissolved, or thematrix layer composition may contain asenapine particles, preferablyconstituted of asenapine free base.

As outlined above, the amount of asenapine in the TTS is believed to beimportant for a good release of the active, and can be e.g. adjusted bythe asenapine concentration. Thus, in certain embodiments, the amount ofasenapine in the matrix layer composition ranges from 2 to 20%,preferably from 3 to 15% and more preferably from 4 to 12% of the matrixlayer composition.

In certain embodiments, the asenapine has a purity of at least 95%,preferably of at least 98% and more preferably of at least 99% asdetermined by quantitative HPLC.

Quantitative HPLC may be performed with Reversed-Phase-HPLC with UVdetection. In particular, the following conditions can be used if HPLCis performed isocratically:

-   Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase L1)    -   Kromasil C18 125 mm×4.0 mm; 5 μm or equivalent-   Mobile phase: KH₂PO₄/Methanol/TEA (45:55:0.1; v:v:v); pH 2.5±0.05    (TEA=triethylamine)-   Gradient: isocratic-   Flux: 1.0 ml-   Injection volume: 30 μl-   Column temperature: 40° C.-   Wavelength: 225 nm, 270 nm and 3-D-field; Evaluation is performed at    270 nm-   Run time: 10 min    Furthermore, the following conditions can be used if HPLC is    performed with a gradient:-   Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase L1)    -   Kinetex C18 EVO 100 mm×4.6 mm; 2.1 μm or equivalent-   Mobile phase: A: 0.02 mol KH₂PO₄ Buffer/Methanol/TEA (70:30:0.1;    v:v:v) adj. to    -   pH 2.5    -   B: 0.02 mol KH₂PO₄ Buffer/Methanol/TEA (30:70:0.1; v:v:v); adj.        to    -   pH 2.5 (TEA=triethylamine)-   Flux: 1.0 ml-   Injection volume: 30 μl-   Column temperature: 40° C.-   Wavelength: 225 nm, 270 nm and 3-D-field; Evaluation is performed at    225 nm-   Run time: 32 min

Gradient profile:  0.00 min: A: 100% B: 0% 12.00 min: A: 40% B: 60%18.00 min: A: 0% B: 100% 27.00 min: A: 0% B: 100% 27.01 min: A: 100% B:0% 32.00 min: A: 100% B: 0%

Polymer

As outlined above, the TTS according to a specific embodiment of thepresent invention comprises a self-adhesive layer structure comprisingan asenapine-containing matrix layer consisting of a matrix layercomposition, wherein the matrix layer composition comprises a polymer.

This polymer provides for sufficient cohesion of the matrix layer.According to certain embodiments the polymer may also provide forsufficient adhesion. In those embodiments the polymer is selected frompressure sensitive adhesive polymers.

In a preferred embodiment, the polymer is selected frompressure-sensitive adhesive polymers.

Polymers which are suitable as the polymer in accordance with theinvention are polysiloxanes, polyisobutylenes, styrene-isoprene-styreneblock copolymers and acrylic polymers.

Corresponding commercial products are available e.g. under the brandnames Bio-PSAs (polysiloxanes), Oppanol B10/B100 (a polyisobutylenepolymer, 85:15), JSR-SIS (a styrene-isoprene-styrene copolymer) orDuro-Tak™ (acrylic polymers, see below for details).

Suitable polyisobutylenes according to the invention are available underthe tradename Oppanol®. Combinations of high-molecular weightpolyisobutylenes (B100/B80) and low-molecular weight polyisobutylenes(B10, B11, B12, B13) may be used. Suitable ratios of low-molecularweight polyisobutylene to high-molecular weight polyisobutylene are inthe range of from 100:1 to 1:100, preferably from 95:5 to 40:60, morepreferably from 90:10 to 80:20. Typically, the low molecular molecularweight polyisobutylene has a viscosity average molecular weight of from10,000 to 70,000 g/mol and/or a weight average molecular weight of from10,000 to 70,000 g/mol, and the high molecular weight polyisobutylenehas a viscosity average molecular weight of from 1,000,000 to 1,200,000g/mol and/or a weight average molecular weight of from 1,400,000 to1,600,000 g/mol. A preferred example for a polyisobutylene combinationis B10/B100 in a ratio of 85/15 or 90/10. Oppanol® B100 has a viscosityaverage molecular weight M_(v) of 1,110,000, and a weight averagemolecular weight M_(w) of 1,550,000. Oppanol® B10 has a viscosityaverage molecular weight M_(v) of 40,000, and a weight average molecularweight M_(w) of 36,000. In certain embodiments, polybutene may be addedto the polyisobutylenes.

Preferably, the polymer is selected from acrylic polymers, wherein theacrylic polymers comprise or do not comprise functional groups.

Corresponding commercial products are available e.g. under the brandnames Duro-Tak™ 387-2287 (an acrylic copolymer comprising hydroxylgroups), Duro-Tak™ 387-2516 (an acrylic copolymer comprising hydroxylgroups), Duro-Tak™ 387-2051 (an acrylic copolymer comprising carboxylicacid groups), Duro-Tak™ 387-2353 (an acrylic copolymer comprisingcarboxylic acid groups), Duro-Tak™ 387-4098 (an acrylic copolymercomprising no functional groups) and Duro-Tak™ 387-9301 (an acryliccopolymer comprising no functional groups).

In certain embodiments, the polymer is selected from acrylic polymerscomprising functional groups wherein the functional groups are selectedfrom hydroxyl groups, carboxylic acid groups, neutralized carboxylicacid groups and mixtures thereof. Preferably, the functional groups arelimited to hydroxyl groups.

In certain embodiments, the polymer is selected from acrylic polymerswhich do not comprise carboxylic acid groups or neutralized carboxylicacid groups or both groups, and preferably the polymer is selected fromacrylic polymers which do not comprise acidic groups.

In further preferred embodiments, the polymer is selected from acrylicpolymers comprising hydroxyl groups and no carboxylic acid groups, andmore preferably, the polymer is a copolymer based on vinyl acetate,2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate andglycidyl-methacrylate.

Such a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate,2-hydroxyethyl-acrylate and glycidyl-methacrylate is commerciallyavailable under the brand names Duro-Tak™ 387-2287 (provided as asolution in ethyl acetate without cross-linking agent) and Duro-Tak™387-2516 (provided as a solution in ethyl acetate, ethanol, n-heptaneand methanol with a titanium cross-linking agent). Thus, depending onthe type of commercially available acrylic polymer used and depending onwhether a cross-linking agent is added to the coating composition, thepolymer in the finalized matrix layer is cross-linked (and preferably iscross-linked by a titanium cross-linking agent) or is not cross-linkedby a cross-linking agent.

In certain other embodiments, the polymer is selected from acrylicpolymers comprising no hydroxyl groups and no carboxylic acid groups,and preferably, the polymer is selected from acrylic polymers comprisingno functional groups.

In further preferred embodiments, the polymer is a copolymer based onmethyl acrylate, 2-ethylhexyl acrylate and t-octyl acylamide, and whichis commercially available under the brand name Duro-Tak™ 387-9301(provided as a solution in ethyl acetate).

In further preferred embodiments, the polymer is a copolymer based on2-ethylhexyl-acrylate and vinyl acetate, which is commercially availableunder the brand name Duro-Tak™ 387-4098 (provided as a solution in ethylacetate).

In certain preferred embodiments, the amount of the polymer ranges from60 to 97%, preferably from 65 to 80% or from 70 to 96% and morepreferably from 75 to 88% or from 91 to 96%, and most preferably from 77to 82% or from 81 to 85% of the matrix layer composition. These amountsare in particular preferred in case the matrix layer composition doesnot comprise any further, additional polymer(s).

However, the matrix layer composition may also comprise a second orfurther, additional polymer(s), and in particular may comprise one ofthe aforementioned polymers as second or further, additional polymer(s).

Additional polymers and additives may also be added to enhance cohesionand/or adhesion.

Certain polymers in particular reduce the cold flow and are thus inparticular suitable as additional polymer. A polymeric matrix may show acold flow, since such polymer compositions often exhibit, despite a veryhigh viscosity, the ability to flow very slowly. Thus, during storage,the matrix may flow to a certain extent over the edges of the backinglayer. This is a problem with storage stability and can be prohibited bythe addition of certain polymers. A basic acrylate polymer (e.g.Eudragit E100 which is a copolymer based on dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate) may e.g. beused to reduce the cold flow. Thus, in certain embodiments, the matrixlayer composition comprises additionally a basic polymer, in particularan amine-functional acrylate as e.g. Eudragit E100.

According to certain embodiments, the total polymer content in thematrix layer composition ranges from 60 to 97%, preferably from 70 to96%, and more preferably from 75 to 95% or from 75 to 90% of the matrixlayer composition. In some embodiments, the total polymer content in thematrix layer composition ranges from 75 to 97%, preferably from 80 to96%, more preferably from 85 to 95% and most preferably from 87 to 92%or from 91 to 95% of the matrix layer composition.

Further Additives

As outlined above, the TTS according to a specific embodiment of thepresent invention comprises a self-adhesive layer structure comprisingan asenapine-containing matrix layer consisting of a matrix layercomposition. In such embodiments, the matrix layer composition of theTTS according to the invention may comprise further excipients oradditives selected from the group consisting of cross-linking agents,solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners,substances for skincare, permeation enhancers, i.e. substances whichinfluence the barrier properties of the stratum corneum in the sense ofincreasing the active agent permeability, pH regulators, andpreservatives. Particularly preferred additives are tackifiers andstabilizers. Such additives may be present in the asenapine-containinglayer in an amount of from 0.001% to 15% of the matrix layer compositionper additive. In a certain embodiment, the total amount of all additivesis from 0.001% to 25% of the matrix layer composition. Hereinafter,where a range for an amount of a specific additive is given, such arange refers to the amount per individual additive.

It should be noted that in pharmaceutical formulations, the formulationcomponents are categorized according to their physicochemical andphysiological properties, and in accordance with their function. Thismeans in particular that a substance or a compound falling into onecategory is not excluded from falling into another category offormulation component. E.g. a certain polymer can be a crystallizationinhibitor but also a tackifier. Some substances may e.g. be a typicalsoftener but at the same time act as a permeation enhancer. The skilledperson is able to determine based on his general knowledge in whichcategory or categories of formulation component a certain substance orcompound belongs to. In the following, details on the excipients andadditives are provided which are, however, not to be understood as beingexclusive. Other substances not explicitly listed in the presentdescription may be as well used in accordance with the presentinvention, and substances and/or compounds explicitly listed for onecategory of formulation component are not excluded from being used asanother formulation component in the sense of the present invention.

The cross-linking agent may be selected from the group consisting ofaluminium and titanium cross-linking agents such as aluminiumacetylacetonate, titanium acetylacetonate or polybutyltitanate, andpreferably is a titanium cross-linking agent. The amount ofcross-linking agent may range from 0.005 to 1%, and preferably from 0.01to 0.1% of the matrix layer composition. The matrix layer compositionmay also comprise a polymer which is self-crosslinking, i.e. comprises across-linking functional group such as glycidyl groups, which reactsupon heating. According to a further specific embodiment, the matrixlayer composition comprises a cross-linking agent as above and aself-crosslinking polymer.

In one embodiment, the matrix layer composition further comprises asolubilizer. The solubilizer preferably improves the solubility of theasenapine in the asenapine-containing layer. Preferred solubilizersinclude, e.g., glycerol-, polyglycerol-, propylene glycol- andpolyoxyethylene-esters of medium chain and/or long chain fatty acids,such as glyceryl monolinoleate, medium chain glycerides and medium chaintriglycerides, non-ionic solubilizers made by reacting castor oil withethylene oxide, and any mixtures thereof which may further contain fattyacids or fatty alcohols; cellulose and methylcellulose and derivativesthereof such as hydroxypropylcellulose and hypromellose acetatesuccinate; various cyclodextrins and derivatives thereof; non-ionictri-block copolymers having a central hydrophobic chain ofpolyoxypropylene flanked by two hydrophilic chains of polyoxyethyleneknown as poloxamers; a polyethylene glycol, polyvinyl acetate andpolyvinylcaprolactame-based graft copolymer, also abbreviated asPVAc-PVCap-PEG and known as Soluplus®; purified grades of naturallyderived castor oil, of polyethylene glycol 400, of polyoxyethylenesorbitan monooleate (such as polysorbate 80) or of propylene glycols;diethylene glycol monoethyl ether; as well as any of the below mentionedsoluble polyvinylpyrrolidones but also insoluble/cross-linkedpolyvinylpyrrolidones also known as crospovidones such as Kollidon® CL,Kollidon® CL-M and Kollidon® CL-SF, and polyvinylpyrrolidone-polyvinylacetate copolymers, also known as copovidones, such as Kollidon® VA64.

However, also the permeation enhancers mentioned below can act assolubilizers. Furthermore, also crystallization inhibitors may act assolubilizers.

Fillers such as silica gels, titanium dioxide and zinc oxide may be usedin conjunction with the polymer in order to influence certain physicalparameters, such as cohesion and bond strength, in the desired way.

In case the matrix layer is required to have self-adhesive propertiesand one or more polymers is/are selected which does/do not providesufficient self-adhesive properties, a tackifier is added. The tackifiermay be selected from polyvinylpyrrolidone (which, due to its ability toabsorb water, is able to maintain the adhesive properties of the matrixlayer and thus can be regarded as a tackifier in a broad sense),triglycerides, polyethylene glycols, dipropylene glycol, resins, resinesters, terpenes and derivatives thereof, ethylene vinyl acetateadhesives, dimethylpolysiloxanes and polybutenes, preferablypolyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone.In certain embodiments, the matrix layer composition comprises atackifier in an amount of from 5 to 15% of the matrix layer composition.

The term “soluble polyvinylpyrrolidone” refers to polyvinylpyrrolidone,also known as povidone, which is soluble with more than 10% in at leastethanol, preferably also in water, diethylene glycol, methanol,n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride,2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol,glycerol, triethanolamine, propionic acid and acetic acid. Examples ofpolyvinylpyrrolidones which are commercially available include Kollidon®12 PF, Kollidont 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 Fsupplied by BASF, or povidone K90F. The different grades of Kollidon®are defined in terms of the K-Value reflecting the average molecularweight of the polyvinylpyrrolidone grades. Kollidon® 12 PF ischaracterized by a K-Value range of 10.2 to 13.8, corresponding to anominal K-Value of 12. Kollidon® 17 PF is characterized by a K-Valuerange of 15.3 to 18.4, corresponding to a nominal K-Value of 17.Kollidon® 25 is characterized by a K-Value range of 22.5 to 27.0,corresponding to a nominal K-Value of 25, Kollidon® 30 is characterizedby a K-Value range of 27.0 to 32.4, corresponding to a nominal K-Valueof 30. Kollidon® 90 F is characterized by a K-Value range of 81.0 to97.2, corresponding to a nominal K-Value of 90. Preferred Kollidon®grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F.

Within the meaning of this invention, the term “K-Value” refers to avalue calculated from the relative viscosity of polyvinylpyrrolidone inwater according to the European Pharmacopoeia (Ph.Eur.) and USPmonographs for “Povidone”.

In certain embodiments, the matrix layer composition comprises astabilizer selected from sodium metabisulfite, ascorbic acid and esterderivatives thereof, butylated hydroxytoluene, tocopherol and esterderivatives thereof such as tocopheryl acetate and tocopheryl linoleate,preferably from tocopherol and ester derivatives thereof and ascorbicacid and ester derivatives thereof, and is more preferably selected fromascorbyl esters of fatty acids and tocopherol, and most preferably isascorbyl palmitate or α-tocopherol. Also particularly preferred is acombination of tocopherol and ascorbyl palmitate. Where the matrix layercomposition comprises a stabilizer, the amount of the stabilizer is from0.001 to 2% of the matrix layer composition.

In one embodiment, the matrix layer composition further comprises asoftener/plasticizer. Exemplary softeners/plasticizers include linear orbranched, saturated or unsaturated alcohols having 6 to 20 carbon atoms,triglycerides and polyethylene glycols.

In one embodiment, the matrix layer composition further comprises asubstance for skincare. Such substances may be used to avoid or reduceskin irritation as determined by assessment of the skin using dermalresponse scores. Suitable substances for skincare include sterolcompounds such as cholesterol, dexpanthenol, alpha-bisabolol, andantihistamines. Substances for skincare are preferably used in amountsof from 1 to 10% of the matrix layer composition.

In certain embodiments, the matrix layer composition comprises apermeation enhancer selected from diethylene glycol monoethyl ether,diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryllactate, dimethylpropylene urea and a mixture of propylene glycolmonoesters and diesters of fatty acids. Such a mixture of propyleneglycol monoesters and diesters of fatty acids is commercially availablee.g. under the brand name Capryol, which is a propylene glycolmonocaprylate (type II), a mixture of propylene glycol monoesters anddiesters of fatty acids with a ratio of >90% monoesters and <10%diesters, wherein the fatty acids mainly consist of caprylic acid.

In certain other embodiments, the matrix layer composition does notcomprise a permeation enhancer selected from oleic acids, triglycerides,oleic alcohols, and mixtures thereof, and in particular the matrix layercomposition does not comprise a permeation enhancer at all. In anotherembodiment, the matrix layer composition does not comprise sodiumacetate or sodium diacetate. In yet another embodiment, theasenapine-containing layer does not comprise a dicarboxylic acid alkalisalt. In yet another embodiment, the matrix layer composition does notcomprise a maleic acid alkali salt.

The matrix layer composition according to the invention may comprise apH regulator. Preferably, the pH regulator is selected from aminederivatives, inorganic alkali derivatives, polymers with basic andacidic functionality, respectively.

Release Characteristics

The TTS in accordance with the invention are designed for transdermallyadministering asenapine to the systemic circulation for a predefinedextended period of time.

In one aspect, the TTS according to the invention provide a mean releaserate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably of1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, and morepreferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/hover at least 24 hours of administration, preferably over at least 48hours of administration, more preferably over at least 72 hours ofadministration, and most preferably over at least 84 hours ofadministration.

According to certain embodiments, the TTS according to the inventionprovide a cumulative skin permeation rate of asenapine at hour 48 or athour 72 as measured in a Franz diffusion cell with dermatomed human skinof 1 μg/(cm² h) to 20 μg/(cm² h), preferably of 2 μg/(cm² h) to 15μg/(cm² h) and more preferably of 4 μg/(cm² h) to 12 μg/(cm² h).

In specific embodiments of the invention, the TTS according to theinvention as described above provides a skin permeation rate ofasenapine as measured in a Franz diffusion cell with dermatomed humanskin of

0 μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours,

2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 24 to hour 32,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour 48,

2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour 72.

In certain embodiments, the transdermal therapeutic system according tothe invention provides a cumulative permeated amount of asenapine asmeasured in a Franz diffusion cell with dermatomed human skin of 0.05mg/cm² to 1.0 mg/cm², preferably of 0.1 mg/cm² to 0.7 mg/cm² over a timeperiod of 48 hours.

In certain embodiments, the transdermal therapeutic system according tothe invention provides a cumulative permeated amount of asenapine asmeasured in a Franz diffusion cell with dermatomed human skin of 0.1mg/cm² to 2.0 mg/cm², preferably 0.2 mg/cm² to 1.0 mg/cm² over a timeperiod of 72 hours.

Method of Treatment/Medical Use

In accordance with a specific aspect of the present invention, the TTSaccording to the invention is for use in a method of treatment, and inparticular in a method of treating a human patient.

In certain embodiments, the TTS according to the invention is preferablyfor use in a method of treating psychosis, and more preferably for usein a method of treating one or more conditions selected fromschizophrenia, bipolar disorder, posttraumatic stress disorder, majordepressive disorder, dementia related psychosis, agitation and manicdisorder, in particular for use in a method of treating schizophreniaand/or bipolar disorder in a human patient, and in particular for use ina method of treating acute manic or mixed episodes of bipolar disorderin a human patient.

In certain embodiments, the TTS according to the invention is for use ina method of treating acute manic or mixed episodes of bipolar disorderin an adult or a pediatric patient 10 to 17 years of age. In certainembodiments, the TTS according to the invention is for use as anadjunctive treatment to lithium or valproate in a method of treatingbipolar disorder in a human patient, in particular an adult. In certainembodiments, the TTS according to the invention is for use as amaintenance monotherapy treatment in a method of treating bipolardisorder in a human patient, in particular an adult.

The TTS according to the invention is further preferably for use in amethod of treating schizophrenia or bipolar disorder in a subject inneed thereof, the method comprising transdermally administering atherapeutically effective amount of asenapine to the subject, whereinthe asenapine is contained in a transdermal therapeutic system for thetransdermal administration of asenapine, and wherein the transdermaltherapeutic system is in contact with at least one body surface on thesubject for at least 48 hours or 2 days or for at least 72 hours or 3days, or for about 48 hours or about 2 days, or about 72 hours or about3 days, or about 84 hours or about 3.5 days.

Within the meaning of the present invention, the body surface may belocated at any part of the body, and is in certain embodiments selectedfrom the upper outer arm, upper chest, upper back or the side of thechest.

The TTS may be further for use in a method of treatment with a dosinginterval of at least 24 hours or 1 day, at least 48 hours or 2 days, orat least 72 hours or 3 days, and/or with a dosing interval of up to 168hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days.The dosing interval may in particular be 24 hours or 1 day, 48 hours or2 days, or 84 hours or 3.5 days.

Accordingly the invention is also related to TTS for use in a method oftreatment, and in particular for use in a method of treatingschizophrenia and/or bipolar disorder, and in particular acute manic ormixed episodes of bipolar disorder, in an around-the-clock treatmentwith a once-a-day TTS exchange mode (dosing interval of 24 hours or 1day), a twice-a-week TTS exchange mode (dosing interval of 84 hours or3.5 days) or a once-a-week TTS exchange mode (dosing interval of 168hours, or 7 days).

The TIS according to the invention is further preferably for use in amethod of treating a patient, wherein the transdermal therapeutic systemprovides a reduction in at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine.

Relative to an equivalent dose of sublingual asenapine should beunderstood as a comparison in the incidence and intensity of sideeffects in a clinical study when using a dose of transdermal andsublingual asenapine that leads substantially to the same blood plasmaexposure of asenapine.

In another embodiment, the TTS according to the invention may also befor use in a method of reducing, in a patient, at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine.

In such a method of treating a patient or in such a method of reducingat least one asenapine-related side effect, but also in all thetransdermal therapeutic systems for use in a method of treatment, thetransdermal therapeutic systems for use in a method of reducing at leastone asenapine-related side effect, the methods of treatment and methodsof reducing at least one asenapine-related side effect as well as theasenapine for use in a method of treating a human patient as will bedescribed below, the following may generally further apply:

(i) The at least one asenapine-related side effect is in particularfatigue, somnolence, dizziness, oral hypoaesthesia, or any combinationthereof.

(ii) As these side effects are reduced, in one embodiment, the inventivemethods and transdermal therapeutic systems for use in the methods arein particular suitable for a human patient already suffering from such acondition, i.e. suffering from fatigue, somnolence, dizziness, or anycombination thereof.

(iiii) Further, the incidence of the at least one asenapine-related sideeffect relative to an equivalent dose of sublingual asenapine may bereduced by at least about 30%, at least about 40%, at least about 70% orat least about 80%, and/or the intensity of the at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine may be reduced. The intensity of a side effect canbe determined e.g. by classifying the side effects on a scale indicating“mild”, “moderate” or “severe” intensity, and a reduction of theintensity can be quantified by comparing the median intensity.

(iv) In such embodiments, the at least one asenapine-related side effectmay be fatigue and the incidence of fatigue relative to an equivalentdose of sublingual asenapine may be reduced by at least about 30% or atleast about 40% and/or the intensity of fatigue relative to anequivalent dose of sublingual asenapine may be reduced.

(v) alternatively, the at least one asenapine-related side effect may bedizziness, and the incidence of dizziness relative to an equivalent doseof sublingual asenapine may be reduced by at least about 30%, at leastabout 40%, at least about 70% or at least about 80%.

As concerns the type of side effects, it should be noted that fatigueand somnolence, while designating clinically different conditions, havecommon and/or similar symptoms and may be therefore difficult todistinguish, in particular if not followed on a long term.

In accordance with another specific aspect, the present invention isalso related to a method of treatment, and in particular a method oftreating a human patient.

The invention is in particular related to a method of treatingpsychosis, and in particular to a method of treating one or moreconditions selected from schizophrenia, bipolar disorder, posttraumaticstress disorder, major depressive disorder, dementia related psychosis,agitation and manic disorder, and preferably to a method of treatingschizophrenia and/or bipolar disorder in a human patient, and inparticular acute manic or mixed episodes of bipolar disorder includingapplying a transdermal therapeutic system according to the invention tothe skin of a human patient.

In certain embodiments, the invention is also related to a method oftreating acute manic or mixed episodes of bipolar disorder in an adultor a pediatric patient 10 to 17 years of age. In certain embodiments,the invention is also related to a method of treating bipolar disorderin a human patient, in particular an adult, as an adjunctive treatmentto lithium or valproate. In certain embodiments, the invention is alsorelated to a maintenance monotherapy treatment in a method of treatingbipolar disorder in a human patient, in particular an adult.

The invention is further preferably also related to a method of treatingschizophrenia or bipolar disorder in a subject in need thereof, themethod comprising transdermally administering a therapeuticallyeffective amount of asenapine to the subject, wherein the asenapine iscontained in a transdermal therapeutic system for the transdermaladministration of asenapine, and wherein the transdermal therapeuticsystem is in contact with at least one body surface (as defined above)on the subject for at least 48 hours or 2 days or for at least 72 hoursor 3 days, or for about 48 hours or about 2 days, or about 72 hours orabout 3 days, or about 84 hours or about 3.5 days.

The invention is also related to a method of treatment by applying atransdermal therapeutic system according to the invention for at least24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or3 days, and/or for up to 168 hours or 7 days, up to 120 hours or 5 days,or up to 96 hours or 4 days to the skin of a human patient. Thetransdermal therapeutic system according to the invention may inparticular be applied for 24 hours or 1 day, 48 hours or 2 days, or 84hours or 3.5 days to the skin of a human patient.

Accordingly the invention is also related to a method of treatment in anaround-the-clock treatment with a once-a-day TTS exchange mode (dosinginterval of 24 hours or 1 day), a twice-a-week TTS exchange mode (dosinginterval of 84 hours or 3.5 days) or a once-a-week TTS exchange mode(dosing interval of 168 hours, or 7 days).

In such a method, as previously outlined, the transdermal therapeuticsystem may provide a reduction in at least one asenapine-related sideeffect relative to an equivalent dose of sublingual asenapine.

In another embodiment, the present invention is also related to a methodof reducing, in a patient, at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine, the methodcomprising administering a transdermal therapeutic system according tothe invention.

The invention is also related to a method of reducing at least oneasenapine-related side effect in a patient being treated with sublingualasenapine therapy, the method comprising

-   -   a) discontinuing sublingual asenapine therapy; and    -   b) administering a transdermal therapeutic system according to        the invention to the skin of the patient, wherein the        transdermal therapeutic system provides a reduction in at least        one asenapine-related side effect relative to an equivalent dose        of sublingual asenapine.

In such a method, the transdermal therapeutic system may deliver anamount of asenapenaine equivalent to the amount of asenapine originallyprovided by the sublingual asenapine therapy.

The inventors have surprisingly shown that a relatively constantasenapine blood plasma concentration can be maintained for an extendedperiod of time by transdermal delivery of asenapine.

Thus, in accordance with one specific aspect, the present invention isrelated to asenapine for use in a method of treating a human patient bytransdermal administration of asenapine for a dosing interval of atleast 48 hours or 2 days or for a dosing interval of at least 72 hoursor 3 days.

In such embodiments, the dosing interval may be up to 168 hours or 7days, up to 120 hours or 5 days, or up to 96 hours or 4 days, and inparticular may be 48 hours or 2 days, or 72 hours or 3 days, or 84 hoursor 3.5 days.

Further, the asenapine is preferably for use in a method of treatingpsychosis, and in particular for use in a method of treating one or moreconditions selected from schizophrenia, bipolar disorder, posttraumaticstress disorder, major depressive disorder, dementia related psychosis,agitation and manic disorder, or for use in a method of treatingschizophrenia and/or bipolar disorder, more preferably bipolar disorderand in particular acute manic or mixed episodes of bipolar disorder. Theasenapine is also preferably for use in a method of treating acute manicor mixed episodes of bipolar disorder in an adult or a pediatric patient10 to 17 years of age, for use as an adjunctive treatment to lithium orvalproate or for use as maintenance monotherapy treatment in a method oftreating bipolar disorder in a human patient, in particular an adult.

The asenapine is further preferably for use in a method of treatingschizophrenia or bipolar disorder in a subject in need thereof, themethod comprising transdermally administering a therapeuticallyeffective amount of asenapine to the subject, wherein the asenapine iscontained in a transdermal therapeutic system for the transdermaladministration of asenapine, and wherein the transdermal therapeuticsystem is in contact with at least one body surface (as defined above)on the subject for at least 48 hours or 2 days or for at least 72 hoursor 3 days, or for about 48 hours or about 2 days, or about 72 hours orabout 3 days, or about 84 hours or about 3.5 days.

The relatively constant asenapine blood plasma concentration can bedescribed by several pharmacokinetic parameters as obtained in an invivo clinical study on human subjects.

Thus, in certain embodiments, the present invention is related toasenapine for use in a method of treating a human patient by transdermaladministration of asenapine as described above,

-   -   providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to        20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h,        preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000        μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to        625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24        h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to        0.417 mg/h or 83 to 417 μg/h over at least 48 hours or 2 days of        administration, or providing by transdermal delivery a mean        release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to        20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21        to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h,        1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625        mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0        to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h,        0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 72 hours or        3 days of administration, or providing by transdermal delivery a        mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to        20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21        to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h,        1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625        mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0        to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h,        0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 84 hours or        3.5 days of administration.

Further, in certain embodiments, the present invention is related toasenapine for use in a method of treating a human patient by transdermaladministration of asenapine as described above,

-   -   providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300        (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably        from 30 to 200 (ng/ml) h, or    -   providing by transdermal delivery an AUC₀₋₇₂ from 30 to 400        (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably        from 50 to 300 (ng/ml) h, or    -   providing by transdermal delivery an AUC₀₋₈₄ from 35 to 450        (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably        from 60 to 350 (ng/ml) h.

Still further, in certain embodiments, the present invention is relatedto asenapine for use in a method of treating a human patient bytransdermal administration of asenapine as described above,

-   -   providing by transdermal delivery a C_(max) to C₄₈ ratio of less        than 2.0, preferably of less than 1.5 and more preferably of        less than 1.3, or    -   providing by transdermal delivery a C_(max) to C₇₂ ratio of less        than 3.0, preferably of less than 2.5 and more preferably of        less than 2.0, or    -   providing by transdermal delivery a C_(max) to C₈₄ ratio of less        than 3.5, preferably of less than 3.0, more preferably of less        than 2.5 and most preferably of less than 2.0.

Still further, in certain embodiments, the present invention is relatedto asenapine for use in a method of treating a human patient bytransdermal administration of asenapine as described above.

-   -   providing by transdermal delivery a Cm value of from 0.5 to 10        ng/ml and preferably of from 1 to 8 ng/ml.

In further embodiments, the present invention is further related toasenapine for use in a method of treating a human patient as outlinedabove, wherein at least one asenapine-related side effect relative to anequivalent dose of sublingual asenapine is reduced.

In accordance with another specific aspect, the present invention isrelated to a transdermal therapeutic system for the transdermaladministration of asenapine for use in a method of treating a humanpatient for a dosing interval of at least 48 hours or 2 days or for adosing interval of at least 72 hours or 3 days.

In such embodiments, the dosing interval may be up to 168 hours or 7days, up to 120 hours or 5 days, or up to 96 hours or 4 days, and inparticular may be 48 hours or 2 days, or 72 hours or 3 days, or 84 hoursor 3.5 days.

Such a transdermal therapeutic system for use in a method of treating ahuman patient as described above preferably comprises a self-adhesivelayer structure containing a therapeutically effective amount ofasenapine.

Further, the transdermal therapeutic system is preferably for use in amethod of treating psychosis, and in particular for use in a method oftreating one or more conditions selected from schizophrenia, bipolardisorder, posttraumatic stress disorder, major depressive disorder,dementia related psychosis, agitation and manic disorder, or for use ina method of treating schizophrenia and/or bipolar disorder, morepreferably bipolar disorder and in particular acute manic or mixedepisodes of bipolar disorder. The transdermal therapeutic system is alsopreferably for use in a method of treating acute manic or mixed episodesof bipolar disorder in an adult or a pediatric patient 10 to 17 years ofage, for use as an adjunctive treatment to lithium or valproate or foruse as maintenance monotherapy treatment in a method of treating bipolardisorder in a human patient, in particular an adult.

The transdermal therapeutic system is further preferably for use in amethod of treating schizophrenia or bipolar disorder in a subject inneed thereof, the method comprising transdermally administering atherapeutically effective amount of asenapine to the subject, whereinthe asenapine is contained in a transdermal therapeutic system for thetransdermal administration of asenapine, and wherein the transdermaltherapeutic system is in contact with at least one body surface (asdefined above) on the subject for at least 48 hours or 2 days or for atleast 72 hours or 3 days, or for about 48 hours or about 2 days, orabout 72 hours or about 3 days, or about 84 hours or about 3.5 days.

Thus, in certain embodiments, the present invention is related to atransdermal therapeutic system for the transdermal administration ofasenapine for use in a method of treating a human patient as describedabove,

-   -   providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to        20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h,        preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000        μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to        625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24        h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to        0.417 mg/h or 83 to 417 μg/h over at least 48 hours or 2 days of        administration, or providing by transdermal delivery a mean        release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to        20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21        to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h,        1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625        mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0        to 10 mg/24 h, 2,000 to 10.000 μg/day, 2,000 to 10,000 μg/24 h,        0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 72 hours or        3 days of administration, or providing by transdermal delivery a        mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to        20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21        to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h,        1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625        mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0        to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h,        0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 84 hours or        3.5 days of administration.

Further, in certain embodiments, the present invention is related to atransdermal therapeutic system for the transdermal administration ofasenapine for use in a method of treating a human patient as describedabove.

-   -   providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300        (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably        from 30 to 200 (ng/ml) h, or    -   providing by transdermal delivery an AUC₀₋₇₂ from 30 to 400        (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably        from 50 to 300 (ng/ml) h, or    -   providing by transdermal delivery an AUC₀₋₈₄ from 35 to 450        (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably        from 60 to 350 (ng/ml) h.

Still further, in certain embodiments, the present invention is relatedto a transdermal therapeutic system for the transdermal administrationof asenapine for use in a method of treating a human patient asdescribed above,

-   -   providing by transdermal delivery a C_(max) to C₄₈ ratio of less        than 2.0, preferably of less than 1.5 and more preferably of        less than 1.3, or    -   providing by transdermal delivery a C_(max), to C₇₂ ratio of        less than 3.0, preferably of less than 2.5 and more preferably        of less than 2.0, or    -   providing by transdermal delivery a C_(max) to C₈₄ ratio of less        than 3.5, preferably of less than 3.0, more preferably of less        than 2.5 and most preferably of less than 2.0.

Still further, in certain embodiments, the present invention is relatedto a transdermal therapeutic system for the transdermal administrationof asenapine for use in a method of treating a human patient asdescribed above,

-   -   providing by transdermal delivery a C_(max) value of from 0.5 to        10 ng/ml and preferably of from 1 to 8 ng/ml.

In all such embodiments, as previously described, the TTS may be for usein a method of treating a human patient, wherein the transdermaltherapeutic system provides a reduction in at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine.

In accordance with yet another specific aspect, the present invention isrelated to a method of treating a human patient by transdermaladministration of asenapine for a dosing interval of at least 48 hoursor 2 days or for a dosing interval of at least 72 hours or 3 days.

In such embodiments, the dosing interval may be up to 168 hours or 7days, up to 120 hours or 5 days, or up to 96 hours or 4 days, and inparticular may be 48 hours or 2 days, or 72 hours or 3 days, or 84 hoursor 3.5 days.

Such a method of treating a human patient by transdermal administrationof asenapine as described above preferably includes applying atransdermal therapeutic system for the transdermal administration ofasenapine for at least 48 hours or 2 days, for at least 72 hours or 3days, for 48 hours or 2 days, for 72 hours or 3 days, or for 84 hours or3.5 days to the skin of a patient.

Such a transdermal therapeutic system for the transdermal administrationof asenapine preferably comprises a self-adhesive layer structurecontaining a therapeutically effective amount of asenapine.

Further, the method described above is preferably a method of treatingpsychosis, and in particular a method of treating one or more conditionsselected from schizophrenia, bipolar disorder, posttraumatic stressdisorder, major depressive disorder, dementia related psychosis,agitation and manic disorder, or a method of treating schizophreniaand/or bipolar disorder, more preferably bipolar disorder and inparticular acute manic or mixed episodes of bipolar disorder.

In certain embodiments, the method is also preferably a method oftreating acute manic or mixed episodes of bipolar disorder in an adultor a pediatric patient 10 to 17 years of age, or a method of treatingbipolar disorder in a human patient, in particular an adult, as anadjunctive treatment to lithium or valproate or as a maintenancemonotherapy treatment.

In certain embodiments, the method is further preferably a method oftreating schizophrenia or bipolar disorder in a subject in need thereof,the method comprising transdermally administering a therapeuticallyeffective amount of asenapine to the subject, wherein the asenapine iscontained in a transdermal therapeutic system for the transdermaladministration of asenapine, and wherein the transdermal therapeuticsystem is in contact with at least one body surface (as defined above)on the subject for at least 48 hours or 2 days or for at least 72 hoursor 3 days, or for about 48 hours or about 2 days, or about 72 hours orabout 3 days, or about 84 hours or about 3.5 days.

The relatively constant asenapine blood plasma concentration can bedescribed by several pharmacokinetic parameters as obtained in an invivo clinical study on human subjects.

Thus, in certain embodiments, the present invention is related to amethod of treating a human patient as described above,

-   -   providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to        20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h,        preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000        μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to        625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24        h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to        0.417 mg/h or 83 to 417 μg/h over at least 48 hours or 2 days of        administration, or providing by transdermal delivery a mean        release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to        20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21        to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h,        1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625        mg h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0        to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h,        0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 72 hours or        3 days of administration, or providing by transdermal delivery a        mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to        20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21        to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h,        1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625        mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0        to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h,        0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 84 hours or        3.5 days of administration.

Further, in certain embodiments, the present invention is related to amethod of treating a human patient as described above,

-   -   providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300        (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably        from 30 to 200 (ng/ml) h, or    -   providing by transdermal delivery an AUC₀₋₇₂ from 30 to 400        (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably        from 50 to 300 (ng/ml) h, or    -   providing by transdermal delivery an AUC₀₋₈₄ from 35 to 450        (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably        from 60 to 350 (ng/ml) h.

Still further, in certain embodiments, the present invention is relatedto a method of treating a human patient as described above,

-   -   providing by transdermal delivery a C_(max) to C₄₈ ratio of less        than 2.0, preferably of less than 1.5 and more preferably of        less than 1.3, or    -   providing by transdermal delivery a C_(max) to C₇₂ ratio of less        than 3.0, preferably of less than 2.5 and more preferably of        less than 2.0, or    -   providing by transdermal delivery a C_(max) to C₈₄ ratio of less        than 3.5, preferably of less than 3.0, more preferably of less        than 2.5 and most preferably of less than 2.0.

Still further, in certain embodiments, the present invention is relatedto a method of treating a human patient as described above, providing bytransdermal delivery a C_(max) value of from 0.5 to 10 ng/ml andpreferably of from 1 to 8 ng/ml.

In such methods as described above, the transdermal therapeutic systemmay provide a reduction in at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine.

In a yet further aspect, the present invention is related to atransdermal therapeutic system for the transdermal administration ofasenapine for use in a method of treating a human patient, wherein

the transdermal therapeutic system provides a reduction in at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine, and wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

In another aspect, the present invention is directed to a method oftreating a human patient by transdermal administration of asenapine,wherein at least one asenapine-related side effect relative to anequivalent dose of sublingual asenapine is reduced, and wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

In yet another aspect, the present invention is directed to a method ofreducing, in a human patient, at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine, the methodcomprising transdermal administration of asenapine, wherein the humanpatient is suffering from fatigue, somnolence, dizziness, or anycombination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

In a yet further aspect, the present invention is directed to a methodof reducing at least one asenapine-related side effect in a patient, andin particular a human patient, being treated with sublingual asenapinetherapy, the method comprising

a) discontinuing sublingual asenapine therapy; and

b) transdermal administration of asenapine,

wherein the patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

Process of Manufacture

The invention further relates to a process of manufacture of a matrixlayer for use in a transdermal therapeutic system and a correspondingmatrix layer structure and a corresponding TTS.

In accordance with the invention, the process of manufacture of a matrixlayer for use in a transdermal therapeutic system comprises the stepsof:

-   -   1) combining at least the components asenapine and polymer, in a        solvent to obtain a coating composition;    -   2) coating the coating composition onto the backing layer or        release liner or any intermediate liner; and    -   3) drying the coated coating composition to form the matrix        layer.

In this process of manufacture, preferably in step 1) the asenapine isdissolved to obtain a coating composition.

In the above described process preferably the solvent is selected fromalcoholic solvents, in particular methanol, ethanol, isopropanol andmixtures thereof, and from non-alcoholic solvents, in particular ethylacetate, hexane, n-heptane, petroleum ether, toluene, and mixturesthereof, and more preferably is selected from ethanol and ethyl acetate.

In certain embodiments, the polymer in the above process is an acrylicpolymer and preferably a copolymer based on vinyl acetate,2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate andglycidyl-methacrylate, which is provided as a solution and preferably asa solution in ethyl acetate, n-heptane, methanol or ethanol with asolids content of from 30 to 60% by weight.

In step 3), drying is performed preferably at a temperature of from 50to 90° C., more preferably from 60 to 80° C.

EXAMPLES

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction of the invention. Numerical values provided inthe examples regarding the amount of ingredients in the composition orthe area weight may vary slightly due to manufacturing variability.

Examples 1A-D

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 1a-d are summarized in Table 1.1 below. The formulations arebased on weight percent as also indicated in Table 1.1.

TABLE 1.1 Ex. 1a Ex. 1b Ex. 1c Ex. 1d Ingredient (Trade Amt Solids AmtSolids Amt Solids Amt Solids Name) [g] [%] [g] [%] [g] [%] [g] [%]Asenapine base 0.34 6.72 0.93 12.34 0.93 12.26 1.97 25.93 Acrylicadhesive in ethyl 9.29 93.28 12.14 81.11 12.16 81.07 11.13 74.07acetate. Solids content of 50.5% by weight (Duro-Tak ™ 387-2287)Isopropyl myristate — — 0.49 6.55 — — — — Diethylene glycol — — — — 0.51 6.67 — — monoethyl ether (Transcutol) Ethyl acetate 2.06 — 3.81 — 3.83— 3.79 — Total 11.69  100.00 17.37 100.00 17.43 100.00  16.89 100.00Area Weight [g/m²] 200.1 141.5 136.9 149.0 Asenapine content 1.345 1.7461.678 3.864 [mg/cm²]Preparation of the Coating Composition

For Examples 1a-1c, a beaker was loaded with the asenapine base and withthe solvent (ethyl acetate), and the isopropyl myristate (Example 1b) orthe diethylene glycol monoethyl ether (Example 1c) was added, ifapplicable. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2287was added and the mixture was then stirred at up to 500 rpm until ahomogeneous mixture was obtained (stirring time is 60 min. or longerthroughout the examples, if not indicated otherwise).

For Example 1d, a beaker was loaded with approx. 1.41 g of the asenapinebase and the solvent (ethyl acetate) was added. The acrylic pressuresensitive adhesive was added and the mixture was stirred at approx. 200rpm for approx. 30 min. Further approx. 0.56 g of the asenapine base wasadded in two portions, while stirring continued at approx. 500 rpm forapprox. 30 min.

Coating of the Coating Composition, Example 1a

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 100 μm thickness, whichmay function as release liner) and dried for approx. 10 min at roomtemperature and 20 min at 60° C. The coating thickness gave an areaweight of the matrix layer of 100.1 g/m². A first part of the dried filmwas laminated with a polyethylene terephthalate backing layer (23 μmthickness) to provide a first asenapine-containing self-adhesive layerstructure. A second, unmodified part of the dried film serves as thesecond asenapine-containing self-adhesive layer structure, comprising arelease liner but not a backing layer.

The polyethylene terephthalate film (siliconised, 100 μm thickness,which may function as a release liner) of the first layer structure wasremoved and the adhesive site of the first layer structure was laminatedon the adhesive site of the second layer structure. This results in anasenapine-containing self-adhesive layer structure with an area weightof the matrix layer of 200.1 g/m², with a backing layer and a releaseliner.

Coating of the Coating Composition, Examples 1b-d

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 100 μm thickness, whichmay function as release liner) and dried for approx. 15 min at roomtemperature and 25 min at 60° C. The coating thickness gave an areaweight of the matrix layer of 141.5 g/m² (Example 1b), 136.9 g/m²(Example 1c), and 149.0 g/m² (Example 1d), respectively. The dried filmwas laminated with a polyethylene terephthalate backing layer (23 μmthickness) to provide an asenapine-containing self-adhesive layerstructure.

Preparation of the TTS (Concerning all Examples)

The individual systems (TTS) were then punched out from theasenapine-containing self-adhesive layer structure. In specificembodiments a ITS as described above can be provided with a furtherself-adhesive layer of larger surface area, preferably with roundedcorners, comprising a pressure-sensitive adhesive matrix layer which isfree of active agent. This is of advantage when the TTS, on the basis ofits physical properties alone, does not adhere sufficiently to the skinand/or when the asenapine-containing matrix layer, for the purpose ofavoiding waste, has pronounced corners (square or rectangular shapes).The TTS are then punched out and sealed into pouches of the primarypackaging material.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 1a-d were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknessGoettingen minipig skin (female) was used. A dermatome was used toprepare skin to a thickness of 800 μm, with an intact epidermis for allTTS. Diecuts with an area of 1.156 cm² were punched from the TTS. Theasenapine permeated amount in the receptor medium of the Franz cell(solution containing 60% phosphate buffer pH 5.5, 30% dipropylene glycoland 10% acetonitrile) at a temperature of 32+1° C. was measured and thecorresponding skin permeation rate calculated. The results are shown inTable 1.2 and FIGS. 1a and 1b .

TABLE 1.2 Skin permeation rate with SD [μg/(cm² h)] Ex. 1a Ex. 1b Ex. 1cEx. 1d Elapsed (n = 3) (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SDRate SD Rate SD 0 0 0 0 0 0 0 0 0 4 0.19 0.27 0.46 0.43 0.22 0.16 0.940.32 8 2.04 0.9 3.37 1.4 3.17 0.71 6.11 0.99 12 4.06 1.57 6.65 2.07 5.90.74 11.86 1.15 16 5.61 1.94 9.36 2.19 7.89 1.08 15.54 1 20 6.8 2.1610.95 2.34 9.27 1.03 18.09 0.98 24 7.41 2.17 11.73 2.09 9.59 0.92 18.720.78 32 7.04 1.87 10.8 1.71 9.62 1.08 18.51 0.3 40 7.98 1.75 12.36 1.5410.05 0.51 19.3 1.25 48 7.91 1.6 11.92 1.49 9.89 0.67 18.92 0.69 56 7.641.27 11.16 1.17 9.69 0.52 18.19 1.2 64 7.4 1.1 10.74 1.01 9.25 0.5217.88 0.44 72 6.95 0.97 10.23 0.72 8.69 0.38 17.2 0.14 96 5.29 0.14 / /5.33 0.34 14.6 0.65 120 4.67 0.24 / / 6.43 0.36 13.69 0.86 144 3.99 0.17/ / 5.49 0.13 11.7 0.51 168 3.22 0.29 / / 4.95 0.18 9.98 0.01

Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 1.3 and in FIG. 1c .

TABLE 1.3 Utilization of asenapine after 72 h [%] Example 1a Example 1bExample 1c Example 1d (n = 3) (n = 3) (n = 3) (n = 3) 34.43 40.49 35.8730.18

Examples 2A-D

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 2a-d are summarized in Table 2.1 below. The formulations arebased on weight percent, as also indicated in Table 2.1.

TABLE 2.1 Ex. 2a Ex. 2b Ex. 2c Ex. 2d Ingredient (Trade Amt Solids AmtSolids Amt Solids Amt Solids Name) [g] [%] [g] [%] [g] [%] [g] [%]Asenapine base 0.35 6.86 0.34 6.63  1.34 13.33  1.34 13.33 Acrylicadhesive in ethyl 8.53 85.38  — — 14.13 71.14 14.13 71.14 acetate.Solids content of 50.5% by weight (Duro-Tak ™ 387-2287) Polyisobutyleneadhesive — — 10.7  86.47  — — — — in petroleum ether, bp 80-110° C.Solids content of 40.9% (Oppanol B10/B100, 85/15) Diethylene glycol 0.397.76 — —  1.56 15.53  1.56 15.53 monoethyl ether (Transcutol)Polyvinylpyrrolidone — — 0.35 6.90 — — — — (Kollidon ® 90F) Ethylacetate 2.54 — — — 3.1 — 3.1 — Petroleum ether, bp 80- — — 5.42 — — — —— 110° C. Total  11.81 100.00  16.81  100.00  20.13 100.00  20.13100.00  Area Weight [g/m²] 91.3 85.7 90.15 159.6 Asenapine content 0.6270.568 1.201 2.127 [mg/cm²]Preparation of the Coating Composition

For Examples 2a, c, and d, the coating compositions were prepared asdescribed in Example 1c except that the diethylene glycol monoethylether was added before the solvent ethyl acetate.

For Example 2b, the beaker was loaded with the solvent (petroleum ether)first and the polyisobutylene adhesive was added. Thepolyvinylpyrrolidone (Kollidon® 90 F) was added while stirring atapprox. 200 rpm. The asenapine base was added while stirring at up to1500 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition, Examples 2a-2c

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 100 μm thickness, whichmay function as release liner) and dried for approx. 10 min at roomtemperature and 20 min at 60° C. (Examples 2a and 2c) or at 90° C.(Example 2b). The coating thickness gave an area weight of the matrixlayer of 91.3 g/m² (Example 2a), 85.7 g/m² (Example 2b), and 90.15 g/m²(Example 2c), respectively. The dried film was laminated with apolyethylene terephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the Self-Adhesive Layer Structure, Example 2d

For Example 2d, a double layer self-adhesive layer structure wasprepared as described for Example 1a, starting from two layers asprepared for Example 2c. This results in an asenapine-containingself-adhesive layer structure with an area weight of the matrix layer of159.6 g/m², with a backing layer and a release liner.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 2a-d were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknessGoettingen minipig skin (female) was used. A dermatome was used toprepare skin to a thickness of 800 μm, with an intact epidermis for allTTS. Diecuts with an area of 1.145 cm² were punched from the TTS. Theasenapine permeated amount in the receptor medium of the Franz cell(phosphate buffer solution pH 5.5 with 0.1% saline azide asantibacteriological agent) at a temperature of 32±1° C. was measured andthe corresponding skin permeation rate calculated. The results are shownin Table 2.2 and FIGS. 2a and 2b .

TABLE 2.2 Skin permeation rate with SD [μg/(cm² h)] Ex. 2a Ex. 2b Ex. 2cEx. 2d Elapsed (n = 3) (n = 2) (n = 2) (n = 3) time [h] Rate SD Rate SDRate SD Rate SD 0 0 0 0 0 0 0 0 0 4 0 0 1.28 1.28 0.39 0.39 0 0 8 0.770.55 4.58 2.7 5.14 1.07 2.28 0.69 12 3.2 0.76 9.34 1.12 10.37 0.47 13.555.27 16 5.7 1.99 10.06 1.08 12.81 1.04 15.21 2.23 20 11.49 4.18 9.1 1.6515.16 1.44 26.1 4.67 24 10.62 2.25 9.74 0.27 11.62 0.47 25.37 2.63 327.73 1.47 8.07 0.44 13.67 0.82 19.02 0.41 40 7.28 1.44 7.11 0.41 14.060.46 21.22 2.11 48 7.25 0.55 5.83 0.19 12.77 0.51 20.42 2.13 56 6.110.63 4.48 0.2 11.97 0.66 19.27 1.98 64 / / 3.85 0.44 7.42 0.34 14.540.88 72 3.38 0.97 2.97 0.19 9.55 0.19 15.71 0.75 96 / / / / 6.45 0.1312.98 0.4 120 / / / / 4.25 0.49 11.39 0.47 144 / / / / 2.38 0.44 8.550.23 168 / / / / 1.45 0.38 6.49 0.67Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 2.3 and in FIG. 2c .

TABLE 2.3 Utilization of asenapine after 72 h [%] Example 2a Example 2bExample 2c Example 2d (n = 3) (n = 2) (n = 2) (n = 3) 60.74 76.4 64.7656.93

Examples 2E-J

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 2e-j are summarized in Table 2.4 below. The formulations arebased on weight percent, as also indicated in Table 2.4.

TABLE 2.4 Ingredient (Trade Examples 2e, 2f and 2g Examples 2h, 2i and2j Name) Amt [g] Solids [%] Amt [g] Solids [%] Asenapine base 2.40 5.974.00 10.01 Polyisobutylene adhesive 82.91 84.06 78.38 79.98 in petroleumether, bp 80-110° C. Solids content of 40.8% (Oppanol B10/B100 85/15)Polyvinylpyrrolidone 4.01 9.97 4.01 10.01 (Kollidon ® 90F) Ethanol 12.03— 12.18 — n-heptane 8.15 — 7.47 — Total 109.51 — 106.04 — Ex. 2e Ex. 2fEx. 2g Ex. 2h Ex. 2i Ex. 2j Area Weight [g/m²] 52.8 129.6 188.4 51.6128.2 185.9 Asenapine content 0.32 0.77 1.12 0.52 1.28 1.86 [mg/cm²]Preparation of the Coating Composition

For Example 2b, the beaker was loaded with the polyvinylpyrrolidone(Kollidon® 90 F) first and ethanol was added while stirring at approx.100-200 rpm. The polyisobutylene adhesive was then added while stirringat approx. 400 rpm. Further, the asenapine base was added while stirringat approx. 400 rpm and finally, n-heptane was added while stirring atapprox. 400-500 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition, Examples 2a-2c

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 75 μm thickness, which mayfunction as release liner) and dried for approx. 10 min-20 min at roomtemperature and 20 min-25 min at 80° C. The coating thickness gave anarea weight of the matrix layer of 52.8 g/m² (Example 2e), 129.6 g/m²(Example 2f), 188.4 g/m² (Example 2g), 51.6 g/m² (Example 2h), 128.2g/m² (Example 2i), and 185.9 g/m² (Example 2j), respectively. The driedfilm was laminated with a polyethylene terephthalate backing layer (23μm thickness) to provide an asenapine-containing self-adhesive layerstructure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 2e to 2j were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknesshuman skin from cosmetic surgeries (female abdomen, date of birth 1969)was used. A dermatome was used to prepare skin to a thickness of 800 μm,with an intact epidermis for all TTS. Diecuts with an area of 1.151 cm²were punched from the TTS. The asenapine permeated amount in thereceptor medium of the Franz cell (phosphate buffer solution pH 5.5 with0.1% saline azide as antibacteriological agent) at a temperature of32±1° C. was measured and the corresponding skin permeation ratecalculated. The results are shown in Tables 2.5 and 2.6 and FIG. 2d .

TABLE 2.5 Skin permeation rate with SD [μg/(cm² h)] Ex. 2e Ex. 2f Ex. 2gElapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 1.040.11 1.28 0.16 2.25 1.50 4 5.44 0.18 6.27 0.31 8.82 3.99 8 8.15 0.099.93 0.19 12.31 3.68 12 8.49 0.21 10.97 0.07 13.27 2.44 16 7.62 0.1810.68 0.12 12.15 2.30 20 6.64 0.06 10.19 0.14 12.09 1.31 24 4.59 0.158.10 0.24 9.59 0.87 32 3.22 0.18 7.36 0.05 8.90 0.21 40 2.14 0.13 6.140.11 7.53 0.19 48 1.47 0.12 5.05 0.04 6.44 0.33 56 1.01 0.06 4.11 0.075.65 0.55 64 0.81 0.02 3.42 0.08 5.11 0.63 72 1.04 0.11 1.28 0.16 2.251.50

TABLE 2.6 Skin permeation rate with SD [μg/(cm² h)] Ex. 2h Ex. 2i Ex. 2jElapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 1.510.28 2.47 0.27 1.68 0.12 4 8.42 0.44 10.69 0.31 10.35 0.45 8 13.86 0.7716.43 0.48 17.79 0.68 12 15.01 0.69 17.51 0.66 20.25 0.73 16 13.69 0.5016.90 0.51 20.42 0.56 20 12.12 0.28 16.25 0.42 19.73 0.51 24 7.81 0.1712.65 0.25 16.11 0.14 32 6.23 0.54 12.31 0.49 15.86 0.15 40 4.23 0.6711.20 0.26 14.03 0.16 48 2.82 0.57 9.50 0.14 12.56 0.12 56 1.91 0.457.45 0.77 10.90 0.28 64 1.35 0.29 7.00 0.37 9.77 0.13 72 1.51 0.28 2.470.27 1.68 0.12Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 2.7 and in FIG. 2e .

TABLE 2.7 Utilization of asenapine after 72 h [%] Example ExampleExample Example Example Example 2e 2f 2g 2h 2i 2j (n = 3) (n = 3) (n =3) (n = 3) (n = 3) (n = 3) 81.02 60.84 52.40 87.78 62.49 53.46

Examples 3A-E

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 3a-e are summarized in Table 3.1 below. The formulations arebased on weight percent, as also indicated in Table 3.1.

TABLE 3.1 Ex. 3a Ex. 3b Ex. 3c Ex. 3d Ex. 3e Ingredient Amt Solids AmtSolids Amt Solids Amt Solids Amt Solids (Trade Name) [g] [%] [g] [%] [g][%] [g] [%] [g] [%] Asenapine base 4.00 16.33 1.15 16.35 1.15 16.22 1.1516.39 1.15 16.37 Acrylic adhesive 36.66 75.54 10.26  73.68 11.07  78.849.33 67.14 9.36 67.29 in ethyl acetate. Solids content of 50.5% byweight (Duro-Tak ™ 387- 2287) Diethylene glycol 1.99 8.13 — — — — — — —— monoethyl ether (Transcutol) Polyethylene — — 0.70 9.97 — — — — — —glycol 400 Polyvinylpyrrolidone — — — — 0.35 4.94 — — — — (PovidoneK90F) Diisopropyl — — — — — — 1.16 16.47 — — adipate Propylene glycol —— — — — — — — 1.15 16.34 monocaprylate, type II (Capryol 90) Ethylacetate 25.20 — 4.23 — 3.90 — 4.66 — 4.67 — Total 57.03 100 16.34  10016.47  100 16.30  100    16.32  100    Area Weight [g/m²] 137.3 144.1146.05 152.1 147.6 Asenapine content 2.242 2.356 2.368 2.493 2.417[mg/cm²]Preparation of the Coating Composition

The coating composition of Example 3a was prepared as described inExample 1c.

For Examples 3b, 3d and 3e, a beaker was loaded with the excipientspolyethylene glycol 400, diisopropyl adipate or propylene glycolmonocaprylate type II, as applicable, and with the solvent (ethylacetate). The acrylic pressure sensitive adhesive Duro-Tak™ 387-2287 wasadded and the mixture was then stirred at up to 500 rpm until ahomogeneous mixture was obtained. The asenapine base was added and themixture again stirred at up to 500 rpm until a homogeneous mixture wasobtained.

For Example 3c, a beaker was loaded with the acrylic pressure sensitiveadhesive Duro-Tak™ 387-2287. The solvent (ethyl acetate) was added andthe mixture was stirred at up to 500 rpm. The polyvinylpyrrolidone wasadded and the mixture was then stirred at approx. 500 rpm until ahomogeneous mixture was obtained. Finally, the asenapine base was addedand the mixture again stirred at up to 500 rpm until a homogeneousmixture was obtained.

Coating of the Coating Composition

See Examples 1b-d for the coating process. The coating thickness gave anarea weight of the matrix layer of 137.3 g/m² (Example 3a), 144.1 g/m²(Example 3b), 146.05 g/m² (Example 3c), 152.1 g/m² (Example 3d), and147.6 g/m² (Example 3e) respectively. The dried film was laminated witha polyethylene terephthalate backing layer (23 μm thickness) to providean asenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 3a-e were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknessGoettingen minipig skin was used. A dermatome was used to prepare skinto a thickness of 800 μm, with an intact epidermis for all TTS. Diecutswith an area of 1.156 cm² were punched from the TS. The asenapinepermeated amount in the receptor medium of the Franz cell (phosphatebuffer solution pH 5.5 with 0.1% saline azide as antibacteriologicalagent) at a temperature of 32±1° C. was measured and the correspondingskin permeation rate calculated. The results are shown in Table 3.2 andFIG. 3a .

TABLE 3.2 Skin permeation rate with SD [μg/(cm² h)] Ex. 3a Ex. 3b Ex. 3cEx. 3d Ex. 3e Elapsed (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) time [h]Rate SD Rate SD Rate SD Rate SD Rate SD 0 0 0 0 0 0 0 0 0 0 0 4 2.210.42 0.91 0.5 0.88 0.16 2.29 1.31 1.21 0.5 8 9.7 2.52 5.95 2.31 6.250.93 13.72 5.98 7.75 1.98 12 16.26 4.98 9.95 3.38 11 2.01 22.9 8.39 14.22.45 16 15.33 4.69 11.67 3.77 15.49 1.59 27.02 8.07 17.94 2.93 20 15.424.82 11.69 3.25 19.09 2.81 28.47 8.1 20.22 1.84 24 22.24 3.41 20.37 3.1318.11 1.5 28.93 6.73 20.88 1.78 32 20.32 2.04 18.94 2.54 17.8 1.71 23.744.95 18.65 1.3 40 20.48 1.83 18.89 1.74 17.76 1.94 22.27 3.42 18.68 1.2648 21.67 2.97 17.89 1.06 15.98 0.99 20.53 1.76 18.06 1.12 56 18.05 0.7316.53 0.67 15.52 1.63 18.55 1.15 17.04 0.39Utilization of Asenapine

The utilization of asenapine at 56 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 3.3 and in FIG. 3b .

TABLE 3.3 Utilization of asenapine after 56 h [%] Example 3a Example 3bExample 3e Example 3d Example 3e (n = 3) (n = 3) (n = 3) (n = 3) (n = 3)43.19 34.80 34.64 47.10 37.60

Examples 4A, 4B

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 4a and 4b are summarized in Table 4.1 below. The formulationsare based on weight percent, as also indicated in Table 4.1.

TABLE 4.1 Ex. 4a Ex. 4b Ingredient (Trade Name) Amt [g] Solids [%] Amt[g] Solids [%] Asenapine base 2.72 18.02 1.26 17.81 Acrylic adhesive in29.49 81.98 — — ethyl acetate, ethanol, n-heptane and methanol. Solidscontent of 42.0% by weight (Duro-Tak ™ 387-2516) Acrylic adhesive inethyl — — 10.04 72.12 acetate. Solids content of 50.5% by weight(Duro-Tak ™ 387-2287) Basic butylated — — 0.71 10.07 methacrylatecopolymer (Eudragit ® E100) Ethyl acetate 2.91 4.35 Total 35.12 100.0016.41 100.00 Area Weight [g/m²] 146.7 126.85 Asenapine content 2.6442.259 [mg/cm²]Preparation of the Coating Composition

For Example 4a, a beaker was loaded with the acrylic pressure sensitiveadhesive Duro-Tak™ 387-2516 and with the asenapine. The solvent ethylacetate was added and the mixture was then stirred at approx. 500 rpmuntil a homogeneous mixture was obtained.

For Example 4b, a beaker was loaded with the asenapine and the solventethyl acetate. The acrylic pressure sensitive adhesive Duro-Tak™387-2287 was added and the mixture was then stirred at approx. 500 rpmuntil a homogeneous mixture was obtained. The basic butylatedmethacrylate copolymer Eudragit E100 was added while stirring at up to1000 rpm.

Coating of the Coating Composition

See Examples 1b-d for the coating process. The coating thickness gave anarea weight of the matrix layer of 146.7 g/m² (Example 4a) and 126.85g/m² (Example 4b) respectively. The dried film was laminated with apolyethylene terephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 4a and 4b were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknessGoettingen minipig skin (female) was used. A dermatome was used toprepare skin to a thickness of 800 μm, with an intact epidermis for allTTS. Diecuts with an area of 1.156 cm² were punched from the TTS. Theasenapine permeated amount in the receptor medium of the Franz cell(phosphate buffer solution pH 5.5 with 0.1% saline azide asantibacteriological agent) at a temperature of 32±1° C. was measured andthe corresponding skin permeation rate calculated. The results are shownin Table 4.2 and FIGS. 4a and 4b .

TABLE 4.2 Skin permeation rate with SD [μg/cm² h)] Elapsed Ex. 4a (n =3) Ex. 4b (n = 3) time [h] Rate SD Rate SD 0 0 0 0 0 4 0.57 0.04 0.620.23 8 3.28 0.32 3.07 0.7 12 6.78 0.59 5.97 1.09 16 9.5 0.47 7.87 1.2720 10.21 0.22 9.01 1.17 24 11.4 0.71 9.64 1.09 32 10.6 0.21 9.67 1.02 4012.05 0.26 10.43 0.96 48 12.09 0.36 10.52 0.89 56 12.57 0.78 10.44 0.8364 11.36 0.52 10.53 0.83 72 10.5 1.48 10.62 0.58 96 7.41 2.26 8.96 0.42120 7.6 1.91 8.55 0.43 144 7.23 1.67 8.06 0.46 168 6.6 1.02 7.31 0.58Utilization of Asenapine

The utilization of asenapine at 72 h and 168 h was calculated based onthe cumulative permeated amount at 72 h and the initial asenapinecontent. The results are shown in Table 4.3 and in FIG. 4c .

TABLE 4.3 Utilization of asenapine after 72 h and after 168 h [%]Example Example Example Example 4a -72 h 4a - 168 h 4b - 72 h 4b - 168 h(n = 3) (n = 3) (n = 3) (n = 3) 27.24 53.44 28.46 63.34

Examples 5A-C

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 5a-c are summarized in Table 5.1 below. The formulations arebased on weight percent, as also indicated in Table 5.1.

TABLE 5.1 Ex. 5a Ex. 5b Ex. 5c Amt Solids Amt Solids Amt SolidsIngredient (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base 0.35 6.920.36  6.91 0.34  6.60 Acrylic adhesive in ethyl acetate. 12.61 93.08 — —— — Solids content of 36.90% by weight (Duro-Tak ™ 87-9301) Acrylicadhesive in ethyl acetate. — — 5.82 57.10 5.78 56.98 Solids content of50.5% by weight (Duro-Tak ™ 387-2287) Acrylic adhesive in ethyl acetate.— — 3.73 28.36 — — Solids content of 39.10% by weight (Duro-Tak ™87-4098) Polyisobutylene adhesive in — — — — 4.12 28.49 petroleum ether,bp 80-110° C. Solids content of 40.9% — — — — — — (Oppanol B10/B100,85/15) Diethylene glycol monoethyl — — 0.38  7.63 0.41  7.93 ether(Transcutol) Ethyl acetate 1.36 — 1.96 — 2.17 — Total 14.32 100.0012.26  100.00  12.81  100.00  Area Weight [g/m²] 99.6 102.55 98.4Asenapine content [mg/cm²] 0.689 0.709 0.650Preparation of the Coating Composition

For Example 5a, a beaker was loaded with the asenapine and with theacrylic pressure sensitive adhesive Duro-Tak™ 387-9301. The solventethyl acetate was added in two portions and the mixture was then stirredat approx. 200 rpm until a homogeneous mixture was obtained.

For Example 5b, a beaker was loaded with the acrylic pressure sensitiveadhesive Duro-Tak™ 387-2287, the acrylic pressure sensitive adhesiveDuro-Tak™ 387-4098, with the asenapine and with the diethylene glycolmonoethyl ether. The solvent ethyl acetate was added in two portions andthe mixture was then stirred at approx. 200 rpm until a homogeneousmixture was obtained.

For Example 5c, a beaker was loaded with the polyisobutylene adhesiveOppanol B10/B100 and with the acrylic pressure sensitive adhesiveDuro-Tak™ 387-2287. A first portion (1.50 g) of the solvent ethylacetate was added and the mixture was then stirred at approx. 100 rpmuntil a homogeneous mixture was obtained. The diethylene glycolmonoethyl ether was added and the mixture was then stirred at approx.200 rpm until a homogeneous mixture was obtained. The asenapine base wasadded and the mixture was again stirred at approx. 1000 rpm and theremaining portion of the solvent ethyl acetate (0.67 g) was added whilestirring.

Coating of the Coating Composition

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 100 μm thickness, whichmay function as release liner) and dried for approx. 10 min at roomtemperature and 20 min at 60° C. (Examples 5a and 5b) or at 90° C.(Example 5c). The coating thickness gave an area weight of the matrixlayer of 99.6 g/m² (Example 5a), 102.55 g/m² (Example 5b), and 98.4 g/m²(Example 5c), respectively. The dried film was laminated with apolyethylene terephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 5a-c were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknessGoettingen minipig skin was used. A dermatome was used to prepare skinto a thickness of 800 μm, with an intact epidermis for all TTS. Diecutswith an area of 1.145 cm² were punched from the TTS. The asenapinepermeated amount in the receptor medium of the Franz cell (solutioncontaining 60% phosphate buffer pH 5.5, 30% dipropylene glycol and 10%acetonitrile) at a temperature of 32±1° C. was measured and thecorresponding skin permeation rate calculated. The results are shown inTable 5.2 and FIG. 5a .

TABLE 5.2 Skin permeation rate with SD [μg/(cm² h)] Ex. 5a Ex. 5b Ex. 5cElapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 00 0 0 4 1.4 0.33 1.03 0.27 1.37 0.18 8 3.7 0.59 2.45 0.47 3.85 1.06 125.72 1.25 4.91 0.87 6.83 1.38 16 7.23 0.97 5.7 1.07 7.88 1.59 20 8.10.79 6.81 0.76 8.38 1.59 24 8.58 0.22 7.14 0.38 8.18 1.59 32 7.15 0.266.73 0.19 7.79 1.41 40 7.39 0.33 6.91 0.38 6.89 0.84 48 7.12 0.34 6.960.37 6.42 0.79 56 6.56 0.6 6.51 0.5 5.65 0.31 64 5.82 0.54 5.96 0.475.12 0.01 72 5.32 0.49 5.61 0.46 4.34 0.05Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 5.3 and in FIG. 5b .

TABLE 5.3 Utilization of asenapine after 72 h [%] Example 5a Example 5bExample 5c (n = 3) (n = 3) (n = 3) 65.79 59.57 67.04

Examples 6A-C

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 6a-c are summarized in Table 6.1 below. The formulations arebased on weight percent, as also indicated in Table 6.1.

TABLE 6.1 Ex. 6a Ex. 6b Ex. 6c Amt Solids Amt Solids Amt SolidsIngredient (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base 0.33 6.730.34 6.73 0.34 6.10 Acrylic adhesive in ethyl acetate. 2.15 22.00 4.6946.93 7.00 72.65 Solids content of 50.5% by weight (Duro-Tak ™ 387-2287)Polysiloxane adhesive in n-heptane. 4.88 71.26 3.23 46.34 1.62 21.25Solids content of 72.40% by weight (DOW CORNING ® BIO- PSA Q7-4301)Petroleum ether, bp 80-110° C. 2.53 — — — — — Ethyl acetate — — 2.31 —4.02 — Total 9.89 100.00 10.57  100.00 12.98  100.00 Area Weight [g/m²]93.7 130.2 105.3 Asenapine content [mg/cm²] 0.631 0.876 0.642Preparation of the Coating Composition

A beaker was loaded with the asenapine and with the acrylic pressuresensitive adhesive Duro-Tak™ 387-2287 and with the polysiloxane adhesiveBio-PSA Q7-4301. The solvent (petroleum ether for Example 6a and ethylacetate for Examples 6b and 6c) was added and the mixture was thenstirred at up to 1500 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition

The resulting asenapine-containing coating composition was coated on apolyester film (fluoro polymer coated, 75 μm thickness, which mayfunction as release liner) and dried for approx. 10 min at roomtemperature and 20 min at 90° C. The coating thickness gave an areaweight of the matrix layer of 93.7 g/m² (Example 6a), 130.2 g/m²(Example 6b), and 105.3 g/m² (Example 6c), respectively. The dried filmwas laminated with a polyethylene terephthalate backing layer (23 μmthickness) to provide an asenapine-containing self-adhesive layerstructure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 6a-c were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknessGoettingen minipig skin (female) was used. A dermatome was used toprepare skin to a thickness of 800 μm, with an intact epidermis for allITS. Diecuts with an area of 1.145 cm² were punched from the TTS. Theasenapine permeated amount in the receptor medium of the Franz cell(phosphate buffer solution pH 5.5 with 0.1% saline azide asantibacteriological agent) at a temperature of 32±1° C. was measured andthe corresponding skin permeation rate calculated. The results are shownin Table 6.2 and FIG. 6a .

TABLE 6.2 Skin permeation rate with SD [μg/(cm² h)] Ex. 6a Ex. 6b Ex. 6cElapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 00 0 0 4 2.26 0.19 0 0 0 0 8 7.43 0.04 1.61 0.2 0.37 0.52 12 12.12 0.844.33 1.16 2.7 0.45 16 12.38 0.57 9.63 1.1 5.16 1.81 20 13.05 0.48 12.024.49 7.86 1.18 24 12.12 0.39 14.12 0.95 8.26 1.36 32 10.13 0.42 9.710.92 6.96 1.01 40 8.05 0.4 9.4 1.17 6.67 0.69 48 6.04 0.48 9.07 0.586.96 0.47 56 4.52 0.46 7.16 0.2 6.17 0.43 64 3.3 0.39 / / / / 72 2.390.44 2.94 0.26 4.03 0.7Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 6.3 and in FIG. 6b .

TABLE 6.3 Utilization of asenapine after 72 h [%] Example 6a Example 6bExample 6c (n = 3) (n = 3) (n = 3) 81.21 53.92 53.57

Examples 7A-C

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 7a-c are summarized in Table 7.1 below. The formulations arebased on weight percent, as also indicated in Table 7.1.

TABLE 7.1 Ex. 7c Ex. 7a Ex. 7b Layer 1 Layer 2 Amt Solids Amt Solids AmtSolids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] [g][%] Asenapine base 0.67 13.35 0.67 13.41 0.68 13.58 0.67 13.15 Acrylicadhesive in ethyl 10.41 86.69 — — — — — — acetate. Solids content of42.0% by weight (Duro- Tak ™ 387-2516) Acrylic adhesive in ethyl — —7.93 79.67 8.55 86.42 — — acetate. Solids content of 50.5% by weight(Duro- Tak ™ 387-2287) Polysiloxane adhesive in n- — — — — — — 6.0786.85 heptane. Solids content of 72.40% by weight (DOW CORNING ® BIO-PSAQ7-4301) Isopropylmyristate — — 0.35  6.92 — — — — Ethyl acetate 0.61 —2.72 — 2.37 — 0.58 — Total 11.69 100.00  11.68  100.00  11.60  100.00 7.32 100.00  Area Weight [g/m²] 94.15 99.85 100.9 90.3 Asenapine content1.257 1.339 2.515 [mg/cm²]Preparation of the Coating Composition

For Example 7a, a beaker was loaded with the asenapine base, the acrylicpressure sensitive adhesive Duro-Tak™ 387-2516 was added and the mixturewas then stirred at approx. 250 rpm until a homogeneous mixture wasobtained. The solvent ethyl acetate was added and the mixture againstirred at up to 400 rpm.

For Example 7b, a beaker was loaded with the asenapine base and with thesolvent (ethyl acetate), and the isopropyl myristate was added. Theacrylic pressure sensitive adhesive Duro-Tak™ 387-2287 was added and themixture was then stirred at approx. 400 rpm until a homogeneous mixturewas obtained.

For the first and second layer of Example 7c, a beaker was loaded withthe asenapine base and with the solvent (ethyl acetate), and the acrylicpressure sensitive adhesive Duro-Tak™ 387-2287 or the polysiloxaneadhesive was added, respectively, and the mixture was then stirred atapprox. 400 rpm until a homogeneous mixture was obtained.

Coating of the Coating Composition of Examples 7a and 7b

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 100 μm thickness, whichmay function as release liner) and dried for approx. 10 min at roomtemperature and 20 min at 60° C. (Example 7b) or at 90° C. (Example 7a).The coating thickness gave an area weight of the matrix layer of 94.15g/m² (Example 7a) and 99.85 g/m² (Example 7b), respectively. The driedfilm was laminated with a polyethylene terephthalate backing layer (23μm thickness) to provide an asenapine-containing self-adhesive layerstructure.

Coating of the Coating Composition of Examples 7c

For Example 7c, the resulting asenapine-containing coating compositionswere coated on a polyethylene terephthalate film (siliconised, 100 μmthickness, for Layer 1, or fluoro polymer coated, 75 μm thickness, forLayer 2, which may function as release liner) and dried for approx. 10min at room temperature and 20 min at 60° C. (Layer 1) or at 90° C.(Layer 2). A double layer self-adhesive layer structure was thenprepared as described for Example 11a, with Layer 1 intended to be thelayer contacting the skin (i.e. the dried film of Layer 2 was laminatedwith a polyethylene terephthalate backing layer (23 μm thickness) andLayer 1 was used unmodified).

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 7a-c were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknessGoettingen minipig skin (female) was used. A dermatome was used toprepare skin to a thickness of 800 μm, with an intact epidermis for allITS. Diecuts with an area of 1.156 cm² were punched from the TTS. Theasenapine permeated amount in the receptor medium of the Franz cell(solution containing 60% phosphate buffer pH 5.5, 30% dipropylene glycoland 10% acetonitrile) at a temperature of 32+1° C. was measured and thecorresponding skin permeation rate calculated. The results are shown inTable 7.2 and FIG. 7a .

TABLE 7.2 Skin permeation rate with SD [μg/(cm² h)] Ex. 7a Ex. 7b Ex. 7cElapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 00 0 0 4 1.81 0.71 2.54 2.11 3.35 1.69 8 6.92 2.03 8.64 4.36 12.37 4.1812 9.03 2.27 13.93 5.95 19.68 5.27 16 9.27 2.71 15.86 6.79 21.77 4.63 2011.12 1.03 15.78 5.32 23.17 4.47 24 12.54 3.32 15.39 4.2 22.85 3.29 3210.53 1.47 13.52 2.9 20.4 2.79 40 10.78 1.4 13.25 2.11 20.52 1.54 489.85 0.89 11.72 1.33 18.38 1.4 56 9.04 0.64 10.37 1.09 17.07 0.3 64 8.480.48 9.01 1.09 16.31 1.08 72 7.93 0.19 8.03 1.18 14.52 0.22Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 7.3 and in FIG. 7b .

TABLE 7.3 Utilization of asenapine after 72 h [%] Example 7a Example 7bExample 7c (n = 3) (n = 3) (n = 3) 52.15 60.83 50.51

Examples 8A-C

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 8a-c are summarized in Table 8.1 below. The formulations arebased on weight percent, as also indicated in Table 8.1.

TABLE 8.1 Ex. 8a Ex. 8b Ex. 8c Amt Solids Amt Solids Amt SolidsIngredient (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base 0.7010.00 0.98 7.00 0.49 7.00 Acrylic adhesive in ethyl acetate. 15.17 90.00 31.39 93.00 14.83 87.98 Solids content of 41.5% by weight(Duro-Tak ™ 387-2516) Polyvinylpyrrolidone (Povidone — — — 0.35 5.02K90F) Ethyl acetate 0.46 — 0.21 — — — Ethanol — — — — 0.56 — Total16.33  100.00  32.58 100.00 16.23 100.00 Area Weight [g/m²] 134.8 168.5134.9 Asenapine content [mg/cm²] 1.348 1.180 0.944Preparation of the Coating Composition

For Examples 8a and 8b, a beaker was loaded with the asenapine base andthe solvent ethyl acetate. The acrylic pressure sensitive adhesiveDuro-Tak™ 387-2516 was added and the mixture was then stirred at up to500 rpm (Example 8a) or at approx. 300 rpm (Example 8b), until ahomogeneous mixture was obtained.

For Example 8c, a beaker was loaded with the asenapine base. The acrylicpressure sensitive adhesive Duro-Tak™ 387-2516 was added and the mixturewas then stirred at approx. 300 rpm until a homogeneous mixture wasobtained. The polyvinylpyrrolidone and the solvent ethanol wereconsecutively added while stirring at approx. 300 rpm and approx. 500rpm, respectively.

Coating of the Coating Composition of Examples 8a and 5c

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 100 μm thickness, whichmay function as release liner) and dried for approx. 15 min at roomtemperature and 25 min at 75° C. The coating thickness gave an areaweight of the matrix layer of 134.8 g/m² (Example 8a) and 134.9 g/m²(Example 8c), respectively. The dried film was laminated with apolyethylene terephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Coating of the Coating Composition of Example 8b

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 100 μm thickness, whichmay function as release liner) and dried for approx. 15 min at roomtemperature and 25 min at 75° C., and additionally 25 min at 75° C. Adouble layer self-adhesive layer structure was then prepared asdescribed for Example 1a. This results in an asenapine-containingself-adhesive layer structure with an area weight of the matrix layer of168.5 g/m², with a backing layer and a release liner.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 8a-c were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknesshuman skin from cosmetic surgeries (female abdomen, date of birth 1954)was used. A dermatome was used to prepare skin to a thickness of 800 μm,with an intact epidermis for all TTS. Diecuts with an area of 1.148 cm²were punched from the TTS. The asenapine permeated amount in thereceptor medium of the Franz cell (phosphate buffer solution pH 5.5 with0.1% saline azide as antibacteriological agent) at a temperature of32±1° C. was measured and the corresponding skin permeation ratecalculated. The results are shown in Table 8.2 and FIGS. 8a and 8b .

TABLE 8.2 Skin permeation rate with SD [μg/(cm² h)] Ex. 8a Ex. 8b Ex. 8cElapsed (n = 3) (n = 3) (n = 3) time [h] Rate SD Rate SD Rate SD 0 0 0 00 0 0 4 1.19 0.62 0.8 0.12 0.77 0.52 8 4.85 1.07 3.41 0.2 2.2 0.37 128.75 1.44 6.38 0.67 4.87 0.64 16 11.06 1.42 8.96 0.61 6.95 0.75 20 12.740.89 10.75 0.92 8.38 0.77 24 13.11 0.78 9.35 0.96 8.93 0.69 32 12.7 0.779.12 0.29 8.7 0.62 40 12.71 0.79 9.97 0.33 8.92 0.6 48 11.94 0.66 9.240.11 8.26 0.34 56 11.31 0.63 8.65 0.24 7.14 0.66 64 9.92 0.44 7.66 0.717.22 0.39 72 9.02 0.3 7.79 0.43 6.27 0.05 96 5.92 0.29 4.64 0.2 3.920.13 120 4.39 0.33 3.95 0.1 2.77 0.19 144 3.13 0.23 2.83 0.04 2.01 0.16Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 8.3 and in FIG. 8c .

TABLE 8.3 Utilization of asenapine after 72 h [%] Example 8a Example 8bExample 8e (n = 3) (n = 3) (n = 3) 55.34 48.92 52.84

Examples 9A, 9B

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 9a and 9b are summarized in Table 9.1 below. The formulationsare based on weight percent, as also indicated in Table 9.1.

TABLE 9.1 Ex. 9a Ex. 9b Ingredient (Trade Name) Amt [g] Solids [%] Amt[g] Solids [%] Asenapine base 0.35 7.00 1.06 7.06 Acrylic adhesive in11.19 93.00 33.61 92.82 ethyl acetate, ethanol, n-heptane and methanol.Solids content of 41.5% by weight (Duro-Tak ™ 387-2516) Ascorbylpalmitate — — 0.02 0.11 Total 11.54 100.00 34.69 100.00 Area Weight[g/m²] 85.8 149.0 Asenapine content 0.601 1.052 [mg/cm²]Preparation of the Coating Composition

A beaker was loaded with the asenapine base and the ascorbyl palmitate(Example 9b), if applicable, and the acrylic pressure sensitive adhesiveDuro-Tak™ 387-2516 was added. The mixture was then stirred at approx.250 rpm (Example 9a) or up to 1000 rpm (Example 9b), until a homogeneousmixture was obtained.

Coating of the Coating Composition

For Example 9a, the resulting asenapine-containing coating compositionwas coated on a polyethylene terephthalate film (siliconised, 100 μmthickness, which may function as release liner) and dried for approx. 10min at room temperature and 15 min at 70° C. For Example 9b, theresulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 75 μm thickness, which mayfunction as release liner) and dried for approx. 15 min at roomtemperature and 25 min at 70° C. The coating thickness gave an areaweight of the matrix layer of 85.8 g/m² (Example 9a) and 149.0 g/m²(Example 9b) respectively. The dried film was laminated with apolyethylene terephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 9a and 9b were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknesshuman skin from cosmetic surgeries (female abdomen, date of birth 1981)was used. A dermatome was used to prepare skin to a thickness of 800 μm,with an intact epidermis for all TTS. Diecuts with an area of 1.149 cm²were punched from the TTS. The asenapine permeated amount in thereceptor medium of the Franz cell (phosphate buffer solution pH 5.5 with0.1% saline azide as antibacteriological agent) at a temperature of32±1° C. was measured and the corresponding skin permeation ratecalculated. The results are shown in Table 9.2 and FIG. 9a .

TABLE 9.2 Skin permeation rate with SD [μg/(cm² h)| Elapsed Ex. 9a (n =3) Ex. 9b (n = 2) time [h] Rate SD Rate SD 0 0 0 0 0 4 0.66 0.07 0.690.02 8 4.61 0.16 4.71 0.01 12 8.14 0.61 9.11 0.13 16 10.49 0.17 11.450.03 20 11.53 0.25 13.04 0.4 24 10.43 0.51 13.07 0.16 32 8.27 0.49 11.580.07 40 7.16 0.36 11.29 0.24 48 6.15 0.07 10.08 0.12 56 4.95 0.34 8.010.36 64 3.15 0.72 8.3 0.09 72 2.92 0.25 7.14 0.1Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 9.3 and in FIG. 9b .

TABLE 9.3 Utilization of asenapine after 72 k [%] Example 9a Example 9b(n = 3) (n = 2) 73.99 62.67

Example 10

Coating Composition

The formulation of the asenapine-containing coating composition issummarized in Table 10.1 below. The formulation is based on weightpercent, as also indicated in Table 10.1.

TABLE 10.1 Ex. 10 Ingredient (Trade Name) Amt [g] Solids [%] Asenapinebase 0.50 4.96 Acrylic adhesive in ethyl acetate, ethanol, 23.01 94.78n-heptane and methanol. Solids content of 41.5% by weight (Duro-Tak ™387-2516) α-Tocopherol 0.03 0.26 Total 23.54 100.00 Area Weight [g/m²]148.35 Asenapine content [mg/cm²] 0.736Preparation of the Coating Composition

A beaker was loaded with the asenapine base and the α-Tocopherol and theacrylic pressure sensitive adhesive Duro-Tak™ 387-2516 was added. Themixture was then stirred at up to 500 rpm until a homogeneous mixturewas obtained.

Coating of the Coating Composition

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 75 μm thickness, which mayfunction as release liner) and dried for approx. 15 min at roomtemperature and 25 min at 70° C. The coating thickness gave an areaweight of the matrix layer of 148.35 g/m². The dried film was laminatedwith a polyethylene terephthalate backing layer (23 μm thickness) toprovide an asenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Example 10 were determined by in vitro experimentsin accordance with the OECD Guideline (adopted Apr. 13, 2004) carriedout with a 10.0 ml Franz diffusion cell. Split thickness human skin fromcosmetic surgeries (male abdomen, date of birth 1955) was used. Adermatome was used to prepare skin to a thickness of 800 μm, with anintact epidermis for all TTS. Diecuts with an area of 1.154 cm² werepunched from the TTS. The asenapine permeated amount in the receptormedium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1%saline azide as antibacteriological agent) at a temperature of 32±1° C.was measured and the corresponding skin permeation rate calculated. Theresults are shown in Table 10.2 and FIG. 10a .

TABLE 10.2 Skin permeation rate with SD [μg/(cm² h] Elapsed Ex. 10 (n =3 time [h] Rate SD 0 0 0 4 0.17 0.05 8 1.8 0.65 24 4.86 1.15 32 6.321.24 48 5.4 0.82 72 4.32 0.51Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The result is shown in Table 10.3 and in FIG. 10b .

TABLE 10.3 Utilization of asenapine after 72 h [%] Example 10 (n = 3)44.36

Example 11

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 11a-d are summarized in Table 11.1 below. The formulations arebased on weight percent, as also indicated in Table 11.1.

TABLE 11.1 Ex. 11a Ex. 11b Ex. 11c Ex. 11d Amt Solids Amt Solids AmtSolids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] [g][%] Asenapine base 4.00 16.38  4.00 16.48  4.00 16.33  4.00 16.48Acrylic adhesive in ethyl 49.26 83.62 — — — — — — acetate, ethanol,n-heptane and methanol. Solids content of 41.5% by weight (Duro-Tak ™387-2516) Acrylic adhesive in ethyl — — 40.16 83.52 36.66 75.54 35.4173.48 acetate. Solids content of 50.5% by weight (Duro-Tak ™ 387-2287)Diethylene glycol — — — —  1.99  8.13 — — monoethyl ether (Transcutol)Basic butylated — — — — — —  2.45 10.07 methacrylate copolymer(Eudragit ® E100) Ethyl acetate 3.75 — 12.32 — 14.37 — 14.66 — Total57.02 100.00  56.48 100.00  57.03 100.00  56.52 100.00  Area Weight[g/m²] 146.0 135.7 137.3 140.3 Asenapine content 2.391 2.237 2.242 2.307[mg/cm²]Preparation of the Coating Composition

For Examples 11a-11c, a beaker was loaded with the asenapine base andwith the solvent (ethyl acetate), and the diethylene glycol monoethylether (Example 11c) was added, if applicable. The acrylic pressuresensitive adhesive Duro-Tak™ 387-2516 (Example 11a) or Duro-Tak™387-2287 (Examples 11b and 11c) was added and the mixture was thenstirred at approx. 500 rpm (Examples 11a and 11b) or approx. 700 rpm(Example 11c) until a homogeneous mixture was obtained.

For Example 11d, a beaker was loaded with the asenapine base and withthe solvent (ethyl acetate). The acrylic pressure sensitive adhesiveDuro-Tak™ 387-2516 was added and the mixture was then stirred at approx.500 rpm until a homogeneous mixture was obtained. The basic butylatedmethacrylate copolymer Eudragit E100 was then added while stirring atapprox. 500 rpm.

Coating of the Coating Composition

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconised, 100 μm thickness, whichmay function as release liner) and dried for approx. 15 min at roomtemperature and 25 min at 60° C. (Examples 11b-11d) or 90° C. (Example11a). The coating thickness gave an area weight of the matrix layer of146.0 g/m² (Example 11a), 135.7 g/m² (Example 11b), 137.3 g/m² (Example11c), and 140.3 g/m² (Example 11d) respectively. The dried film waslaminated with a polyethylene terephthalate backing layer (23 μmthickness) to provide an asenapine-containing self-adhesive layerstructure.

Preparation of the TTS

See example 1.

In Vivo Study Using Goettingen Minipigs

The in vivo releases and the corresponding skin permeation rates of TTSprepared according to Examples 11a-11d were determined by in vivoexperiments using Goettingen minipigs (female, about 6 months,randomized by simple random sample method). Diecuts with an area of 10cm² were punched from the ITS and one Goettingen minipig was used forone TTS formulation. Three drug containing and one placebo TTS (each 10cm²) were used per minipig. The total wear time of all 4 patches perminipig (3 active and 1 placebo) patches was 84 h.

During the study, the minipigs were kept at 22±3° C., at a relativehumidity of 40±15%, lighted from 6 am to 6 μm with calorie reducedbreeding food, sniff, twice daily of about 140-200 g per animal, andwith water ad libitum.

Following the above single dose application of the TTS (3*verum and 1placebo, each 10 cm²), 3 ml blood samples were taken at 0 h, 4 h, 8 h,12 h, 24 h, 32 h, 48 h, 56 h, 72 h, 84 h and 96 h, and the blood sampleswere centrifuged 10 minutes at 2000×g in order to obtain blood plasma.The asenapine blood plasma concentration was determined by an LC methodwith MS/MS detection. AUC values were calculated from the blood plasmaconcentration. After removal of the ITS, the skin condition wasmacroscopically determined and a Draize score obtained based on thescore scheme below. Histopathological examination of the epidermis andthe dermis revealed no morphological or pathological transformationindicating an irritation of the deeper tissue layers. Histologicalresults also show no lesion or removal of stratum corneum. The residualamount of asenapine was determined in the removed TTS by quantitativeHPLC (see above) and the dermally delivered amount of asenapinecalculated as the difference to the initial amount of asenapine includedin the TTS. The results are shown in Tables 11.2, 11.3, and FIG. 11.

TABLE 11.2 Values Ex. 11a Ex. 11b Ex. 11c Ex. 11d Asenapine content of71.8 66.3 67.5 65.9 preclinical sample [mg] Draize* score (3*verum/1/1/1/0 1/1/1/0 1/1/1/0 1/1/1/0 placebo) at 84 and 96 hours Amount ofasenapine dermally 38/27.3 35/23.4 40/27.4 44/28.8 delivered after 84 h[%/mg] *Score schemes for the evaluation of skin irritation potentialaccording to Draize: 0 = No erythema, no edema, 1 = Very slight erythema(barely perceptible), very slight edema (barely perceptible), 2 =Well-defined erythema, Slight edema, 3 = Moderate to severe erythema,moderate edema, 4 = Severe erythema, severe edema.

TABLE 11.3 Asenapine Blood plasma concentration [ng/ml] Time [h] Ex. 11aEx. 11b Ex. 11c Ex. 11d 0 0 0 0 0 4 0.2885 0.3042 0.7746 0.5393 8 2.16911.8003 3.5723 3.7003 12 3.8569 3.3173 5.8001 6.8128 24 3.9563 4.42925.6102 6.3384 32 4.4426 4.0957 5.6204 5.8559 48 4.1034 3.6241 4.83305.6987 56 2.7035 2.8258 2.7434 4.2988 72 4.0017 3.0152 3.4307 4.0930 843.4551 2.5156 3.2065 4.2309 96 0.8566 0.8502 0.5821 1.0256 AUC₍₀₋₂₄₎[(ng/ml) h] 64.4 61.5 97.4 109.5 AUC₍₀₋₄₈₎ [(ng/ml) h] 166.4 157.4 226.0250.7 AUC₍₀₋₇₂₎ [(ng/ml) h] 247.3 229.9 305.7 357.8 AUC₍₀₋₈₄₎ [(ng/ml)h] 292.0 263.1 345.5 407.8 AUC₍₀₋₉₆₎ [(ng/ml) h] 317.9 283.3 368.3 439.3C_(max) [ng/ml] 4.4 4.4 5.8 6.8

Examples 12A, 12B

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 12a and 12b are summarized in Table 12.1 below. Theformulations are based on weight percent, as also indicated in Table12.1.

TABLE 12.1 Ex. 12a Ex. 12b Amt Solids Amt Solids Ingredient (Trade Name)[g] [%] [g] [%] Asenapine base 27.0 6.0 45.0 10.0 Acrylic adhesive inethyl acetate. 903.6 83.5 860.0 79.5 Solids content of about 41.6% byweight (Duro-Tak ™ 387-2516) Polyvinylpyrrolidone (Povidone 45.1 10.045.0 10.0 K90F) α-Tocopherol 2.25 0.5 2.25 0.5 Ethanol denat. (1%(v/v)ethyl 106.8 — 132.3 — ethyl ketone) Total 1084.8 100.0 1084.6 100.0Area weight [g/m²] 148.6 149.6 Asenapine content [mg/cm²] 0.89 1.50Preparation of the Coating Composition

For Examples 12a and 12b, a stainless steel vessel was loaded with theα-tocopherol, the asenapine and the ethanol. The acrylic pressuresensitive adhesive Duro-Tak™ 387-2516 was added and the mixture was thenstirred until a clear solution was obtained (about 20 min). Thepolyvinylpyrrolidone was added slowly while stirring and dissolved understirring until a clear solution was obtained.

Coating of the Coating Composition of Examples 12a and 12b

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (one side siliconized, 75 μm thickness,which may function as release liner) and dried for approx. 15 min at 80°C. The coating thickness gave an area weight of 148.6 g/m² (Ex. 12a) and149.6 g/m² (Ex. 12b), respectively. The dried film was laminated with apolyethylene terephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 12a and 12b were determined by in vitroexperiments in accordance with the OECD Guideline (adopted Apr. 13,2004) carried out with a 7.0 ml Franz diffusion cell. Split thicknesshuman skin from cosmetic surgeries (female abdomen, date of birth 1986)was used. A dermatome was used to prepare skin to a thickness of 800 μm,with an intact epidermis for all TTS. Diecuts with an area of 1.154 cm²were punched from the TTS. The asenapine permeated amount in thereceptor medium of the Franz cell (phosphate buffer solution pH 5.5 with0.1% saline azide as antibacteriological agent) at a temperature of32±1° C. was measured and the corresponding skin permeation ratecalculated. The results are shown in Table 12.2 and FIG. 12a .

TABLE 12.2 Skin permeation rate with SD* [μg/(cm² h)] Elapsed Ex. 12a (n= 3) Ex. 12b (n = 3) time [h] Rate SD Rate SD 0 0.00 0.00 0.00 0.00 20.00 0.00 0.00 0.00 4 0.42 0.01 0.42 0.04 8 1.39 0.08 1.62 0.23 12 3.810.17 4.86 0.46 16 6.07 0.12 7.94 0.78 20 7.19 0.42 10.24 0.72 24 7.800.24 11.90 1.09 32 6.98 0.36 10.78 0.85 40 7.47 0.43 12.11 0.78 487.79** 0.24 11.97 0.65 56 8.20** 0.70 12.25 0.60 64 6.67** 0.18 11.090.20 72 6.10** 0.13 9.83 0.21 *Standard deviation in this Example was,as in all other Examples, calculated based on the n-method. **n = 2.Utilization of Asenapine

The utilization of asenapine at 72 h was calculated based on thecumulative permeated amount at 72 h and the initial asenapine content.The results are shown in Table 12.3 and in FIG. 12b .

TABLE 12.3 Utilization of asenapine after 72 h [%] Example 12a Example12b (n = 2) (n = 3) 51.30 46.20

Examples 13A, 13B

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 13a and 13b are summarized in Table 13.1 below. Theformulations are based on weight percent, as also indicated in Table13.1.

TABLE 13.1 Ex. 13a Ex. 13b Solids Solids Ingredient (Trade Name) Amt [g][%] Amt [g] [%] Asenapine base 54.0 6.0 135 10.0 Acrylic adhesive inethyl acetate. 1820 83.5 7580 79.5 Solids content of about 41.5 % byweight (Duro-Tak ™ 387-2516) Polyvinylpyrrolidone (Povidone 90.0 10.0135 10.0 K90F) α-Tocopherol 4.50 0.5 6.75 0.5 Ethanol denat. (1% (v/v)methyl 211.8 — 414.2 — ethyl ketone) Total 2180.3 100.0 3271.0 100.0Label area weight [g/m²] 140 140 Asenapine content [mg/cm²] 0.88 1.47Preparation of the Coating Composition

For Examples 13a and 13b, the stainless steel vessel was loaded withα-tocopherol. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2516was added and the mixture was then stirred until a clear solution wasobtained. The polyvinylpyrrolidone was added slowly while stirring anddissolved under stirring until a clear solution was obtained. Theasenapine was suspended in the ethanol and transferred to the stainlesssteel vessel. After addition of the asenapine, the mixture was stirredat until a clear, slightly yellow colored solution was obtained.

Coating of the Coating Composition of Examples 13a and 13b

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (one side siliconized, 75 μm thickness,which may function as release liner) and dried for approx. 15 min at 80°C. The coating thickness gave an area weight of about 140 g/m² inaccordance with the label requirements (hereinafter, where reference ismade to a label value, it is understood that the actual value is withina tolerance of +7.5% of the label value). The dried film was laminatedwith a polyethylene terephthalate backing layer (23 μm thickness) toprovide an asenapine-containing self-adhesive layer structure. Residualsolvents amounts fulfilled the requirement the ICH guideline Q3C (R3),i.e. methanol ≥3,000 ppm, ethanol ≤5,000 ppm, ethyl acetate ≤5,000 ppmand n-heptane ≤5,000 ppm.

Preparation of the TTS

Individual systems (TTS) of 10 cm² (Ex. 13a) as well as 15 cm² (Ex. 13b)were then punched out from the asenapine-containing self-adhesive layerstructure.

Example 14

In Vivo Clinical Study

An in vivo clinical trial was conducted to investigate the relativebioavailability of asenapine after transdermal application of theinventive TTS (Examples 13a and 13b) compared to sublingualadministration. The study was performed in accordance with the ethicalprinciples that have their origin in the Declaration of Helsinki.

Trial Design

The trial was conducted in a single center, Phase I, open-label designwith 3 treatments, treatment periods, a fixed treatment sequence in 16healthy male and female subjects, comparing the relative bioavailabilityof asenapine in plasma after single dose transdermal application of theTTS prepared in Examples 13a and 13b to the currently marketedsublingual tablets (Sycrest®, 5 mg).

For each subject, the trial consisted of:

An ambulant screening period in which informed consent was obtained andeligibility of the subjects assessed. Depending on the outcome of thescreening, subjects were included in the trial.

A treatment and observation period consisting of 3 sequential treatmentperiods (each several days long).

An ambulant follow-up visit after the end of last treatment.

Regarding the 3 sequential treatment periods, the subjects receivedsublingual tablets of 5 mg asenapine b.i.d. (=twice daily) (Reference)on the first day of period 1, a single dose of the TTS prepared inExample 13a (3 TTS of 10 cm² each) during period 2 and a single dose ofthe TTS prepared in Example 13b (1 TTS of 15 cm²) during period 3.

Selection of Trial Population

Only subjects meeting all inclusion and none of the exclusion criteriawere included into the treatment phase. The criteria were assessed atscreening and a re-check was performed on Day −1 of Period 1.

Inclusion Criteria

Subjects had to fulfill all of the following criteria to be eligible forparticipation in the treatment period.

1. Subjects who are able to understand and follow instructions duringthe study.

2. Signed informed consent.

3. White.

4. Age ≥18 and ≤55 years.

5. Nonsmoker.

6. In general good physical health as determined by medical and surgicalhistory, physical examination, 12-lead electrocardiogram (ECG), vitalsigns, and clinical laboratory tests.

7. Weight within the normal range according to accepted values for thebody mass index (BMI) within 18.0 to 29.4 kg/m².

8. Normal blood pressure (Systolic Blood Pressure (SBP)≥90≤139 mmHg;Diastolic Blood Pressure ≥55≤89 mmHg) measured after 5 min rest insupine position.

9. A pulse rate of ≥50 and 5≤99 b/min measured after 5 min rest insupine position.

10. ECG recording without clinically significant abnormalities.

11. Having had no febrile or infectious illness for at least 7 daysprior to the first administration.

Exclusion Criteria

To ensure that the subjects are healthy and in a comparable status, thefollowing exclusion criteria were applied.

Lifestyle Restrictions

1. Demonstrating excess in xanthine consumption (more than 5 cups ofcoffee or equivalent per day).

2. More than moderate alcohol consumption (>35 g of ethanol regularlyper day or >245 g regularly per week).

3. Any history of alcohol or drug abuse.

4. Vegetarian.

5. Positive drug screen.

6. Positive alcohol breath test.

7. Consumption of xanthine-containing food or beverages as well asgrapefruit juice or Seville oranges within 48 hours before first dosing.

8. Consumption of char-grilled food, broccoli, or Brussel sprouts within72 h before first dosing.

Prior Medication

9. Use of any medication (self-medication or prescription medication)except hormonal contraception within 4 weeks before first dosing (or atleast 10 times the respective elimination half-life, whichever islonger).

Medical and Surgical History

10. Demonstrating any active physical disease, acute or chronic.

11. Any history of drug hypersensitivity, asthma, urticaria or othersevere allergic diathesis as well as current hay fever.

12. Any history of hypersensitivity of any component of the investigateddosage forms.

13. Any history of chronic gastritis or peptic ulcers.

14. Any history of chronic or recurrent metabolic, renal, hepatic,pulmonary, gastrointestinal, neurological (esp. history of epilepticseizures), endocrinological (esp. diabetes mellitus), immunological,psychiatric or cardiovascular disease, myopathies, dermal diseases, andbleeding tendency.15. Gilbert syndrome.16. Any gastrointestinal complaints within 7 days prior to first dosing.17. Any scars, moles, tattoos, skin irritation or excessive hair growthat the TTS application site.18. Any suicidal ideation of type 2 to 5 on the C-SSRS (ColumbiaSuicidal Severity Rating Scale) in the past 12 months (i.e., activesuicidal thought, active suicidal thought with method, active suicidalthought with intent but without specific plan, or active suicidalthought with plan and intent).Laboratory Examinations19. Laboratory values outside the reference range that are of clinicalrelevance (e.g., suggesting an unknown disease and requiring furtherclinical evaluation assessed by the investigator), especially regardingaspartate aminotransferase (AST), alanine aminotransferase (ALT), gammaglutamyl transpeptidase (GGT).20. Positive test for human immunodeficiency virus (HIV) antibodies/p24antigen.21. Positive Hepatitis B-virus surface antigen (HBsAg) test.22. Positive Anti-hepatitis C-virus antibodies (Anti-HCV) test.Other23. Blood donation within 30 days before signing informed consent tothis trial.24. Participation in the treatment phase of a clinical study 30 days orblocked by the follow-up period of a previous clinical trial beforesigning informed consent to this trial.25. Women of childbearing potential not using a highly effective methodof birth control. Highly-effective methods of birth control are definedas those which result in a low failure rate, i.e. less than 1% per year,when used consistently and correctly (e.g., combination of intrauterinedevice and condom). Female subjects are considered to be of childbearingpotential unless surgically sterilized by hysterectomy or bilateraltubal ligation, or postmenopausal for at least 2 years.26. Pregnant or breastfeeding women.Treatments During the Study

The treatments administered during the study are summarised in Table14.1 below and their characteristics are detailed below.

TABLE 14.1 Dose (Active amount based on label composition of Mode ofTreatment the dosage form) Formulation administration Reference 5 mg pertablet sublingual Two administrations (Period 1) tablet b.i.d. (q12h)TTS of 3*(8.4 mg/10 cm²) TTS Single administration, Example 13a TTSapplied for (Period 2) 3.5 days TTS of 21.0 mg/15 cm² TTS Singleadministration, Example 13b TTS applied for (Period 3) 3.5 days b.i.d. =twice daily; q12h = every 12 h

The reference formulation administered in period 1 contains the activeingredient asenapine maleate and is marketed under the trade nameSycrest-® 5 mg Sublingualtabletten by N.V. Organon, Oss, Netherlands.The pharmacy central number (PZN) is 07728207.

Administration of the Sublingual Tablets (Reference)

Sublingual tablets were administered in the morning and in the eveningof the first day only with 12 h in between the two administrationsaccording to the administration instructions given in the summary ofproduct characteristics. The subjects were instructed to place thetablets under the tongue for at least 10 min to allow dissolving of thesublingual tablet and not to chew or swallow the sublingual tablets.

Application of the TTS

The TTS were applied to intact skin on the upper chest or upper back.Hairs on the application area were trimmed with scissors (not shaved)before application, if necessary. The subjects were instructed to verifythat the skin is free of detergents, oils and fat before TTSapplication. The TTS was placed on the desired position and pressed forat least 30 sec with fingers or the palm to fixate the TTS on the skinsurface. In case of need and to avoid further detachment, the TTS wasadditionally fixated with an adhesive overlay free of active agent. Theoptional adhesive overlay was placed above the TTS in such a way thateach side was equally covered by the adhesive overlay. Afterwards, tofixate the TTS, it was pressed again for at least 30 sec with fingers orthe palm. The TTS were removed after 3.5 days (84 h, Period 2 and Period3). After removal, the used TTS (including the adhesive overlay, ifapplicable) were handled and stored under nitrogen in the refrigeratoruntil they were further analyzed.

Timing of Dose for Each Subject

On the first day of Period 1, no breakfast was served; the subjectsfasted overnight before morning administration. A standardized lunch wasgiven 4 h and dinner approximately 10 h after morning administration.Fluid intake was not allowed from 1 h before until 1 h after morning andevening administration. As food does not interact with the TTS, thesubjects received standardized meals and beverages during in-house daysat customary times during Period 2 and 3. During in-house days, thesubjects were only allowed to consume food or beverages provided by thestudy unit.

Restrictions and Precautions

During the trial, subjects were instructed to abstain from allactivities which may increase body temperature, i.e., physical exertion,sauna, environments with great heat. During the time the ITS were worn,subjects were not allowed to perform any activities which may influenceadhesion of the TTS such as any activities which would increasesweating. Further restrictions on food and beverages intakes were placede.g. in accordance with the exclusion criteria.

Sample Collection and Determination of Blood Plasma Concentrations

Blood samples for the determination of the concentration of asenapineand its metabolites in blood plasma were collected at specified timepoints after administration.

A validated internally standardized liquid chromatography tandem massspectrometry method was used for the determination of the blood plasmaconcentration of asenapine, N-desmethyl-asenapine andasenapine-glucuronide, which was carried out by a GLP (Good LaboratoryPractice)—certified laboratory. Plasma concentrations ofasenapine-glucuronide were only determined for 8 subjects, which had noinfluence on the validity of the results, or the interpretation of thetrial results. The lower limits of quantification (LLOQs) were 0.1 ng/mlfor asenapine and N-desmethyl-asenapine in plasma, and 0.25 ng/ml forasenapine-glucuronide.

Adverse Events (AE)

Adverse events were ascertained by the investigator using non-leadingquestions, noted as spontaneously reported by the subjects to themedical staff or observed during any measurements on all study daysafter administration of the dosage form and rated by a study physician.

Furthermore, suicide risk was monitored. All positive reports during thetrial were documented as adverse events. Suicidal ideation of type 1-3was documented as a non-serious AE. Suicidal ideation of type 4 and 5and all suicidal behavior during the trial were documented as a seriousadverse event (SAE) and reported.

An AE was referred to the treatment and time point after which itoccurred, i.e., any AE occurring before the first dosing was counted asbaseline complaint/pre-treatment AE and is not included in the belowanalysis.

Results and Analysis

All 16 subjects completed period 1 (reference) of the trial. Afterperiod 1 (reference) and before commencing period 2 (Ex. 13a), 1 subjectdropped out. Another subject dropped out during period 3 (Ex. 13b), butcould be assessed for the adverse events analysis. Safety laboratoryparameters, vital signs, and ECG parameters showed no medically relevantchanges. The results of the study are shown in Tables 14.2 to 14.9 andFIGS. 13a to 13 e.

Arithmetic Mean Blood Plasma Concentration of Asenapine

Arithmetic mean values of the asenapine blood plasma concentration basedon all 16 subjects for period 1 and based on the 15 and 14 subjects thatcompleted periods 2 and 3, respectively, along with the standarddeviation values are presented in Table 14.2 as well as FIGS. 13a and13b . AUC values were calculated from the blood plasma concentration.The tri was calculated approximatively as the mean arithmetic value ofthe first point in time when a measurable (i.e. non-zero) asenapineblood plasma concentration was obtained, and the results also indicatedin Table 14.2.

TABLE 14.2 Asenapine blood plasma concentration [ng/ml] Reference Ex.13a Ex. 13b (n = 16) (n = 15) (n = 14) Time [h] mean SD mean SD mean SD0 0.00 0.00 0.00 0.00 0.00 0.00 0.5 2.89 (n = 15) 1.86 — — — — 1 3.581.68 — — — — 2 3.07 1.10 0.02 0.07 0.02 0.07 4 2.85 1.09 0.56 0.58 0.470.34 6 — — 0.92 0.70 0.86 0.44 8 1.48 0.57 1.63 1.09 1.47 0.63 12 0.730.28 2.13 0.98 1.95 0.67 12.5 3.76 1.65 — — — — 13 4.14 1.90 — — — — 143.27 1.56 — — — — 16 2.42 1.12 2.49 1.08 2.23 0.95 20 1.62 0.80 — — — —24 1.27 0.71 2.93 1.14 2.44 0.80 36 0.39 0.18 1.81 (n = 14) 0.61 1.550.37 48 0.30 0.15 2.11 0.59 1.81 0.46 60 0.15 0.12 1.45 (n = 14) 0.341.31 0.29 72 0.14 0.13 1.67 0.37 1.42 0.36 84 0.06 0.09 1.21 (n = 14)0.22 1.09 0.26 86 — — 1.19 0.24 1.02 0.23 88 — — 1.04 0.18 0.88 0.20 960.06 0.09 0.79 0.16 0.68 0.13 108 — — 0.41 0.09 0.36 0.06 120 0.03 0.060.37 0.11 0.30 0.07 132 — — 0.22 0.08 0.19 0.04 144 0.01 0.04 0.20 0.060.17 0.04 156 — — 0.11 0.07 0.09 0.07 168 0.01 0.03 0.11 0.07 0.09 0.07192 — — 0.04 0.06 0.02 0.04 216 — — 0.01 0.03 0.01 0.03 240 — — 0.010.03 0.00 0.00 AUC₍₀₋₄₈₎ — — 95.06  37.20  82.26  25.65  [(ng/ml) h]AUC₍₀₋₇₂₎ — — 135.12  46.05  117.34  33.44  [(ng/ml) h] AUC₍₀₋₈₄₎178.44*  63.59  152.36  48.81  132.38  36.84  [(ng/ml) h] C_(max)[ng/ml] 4.71 1.68 2.93 1.14 2.51 0.90 C₄₈ [ng/ml] — — 2.11 0.59 1.810.46 C₇₂ [ng/ml] — — 1.67 0.37 1.42 0.36 C₈₄ [ng/ml] — — 1.21 0.22 1.090.26 t_(lag) [h] 0.5  0   4.27 1.00 3.71 0.70 Residual amount** 12.0(3*10 cm²) 3.3 (3*10 cm²) 10.3 (15 cm²) 2.3 (15 cm²) [mg/total area ofrelease] Mean release — — 3.8  0.9  3.1  0.6  rate*** [mg/day] *TheAUC₍₀₋₈₄₎ value is calculated for the reference period by multiplyingthe AUC₍₀₋₂₄₎ value by 3.5. **The residual amount is determined byextraction of the active from a sample of the used TTS with anappropriate solvent followed by determination of the active amount usinga validated HPLC method with a UV photometric detector. ***The meanrelease rate is calculated based on the initial asenapine content in theTTS (according to the label composition) applied and on the residualamount in the TTS after 84 hours referring to the total doseadministered (see Table 13.1).Pharmcokinetic Analysis of Asenapine and Metabolites

Based on the plasma concentration time data of asenapine andmetabolites, plasma pharmacokinetic parameters were calculated using noncompartmental procedures and the results are presented in Tables 14.3 to14.5, wherein C_(av) represents the average concentration observedduring the relevant dosing interval (12 h for Period 1/Reference and 84h for Periods 2 and 3/Examples 13a and 13b), and wherein t_(lag)represents the time of first quantifiable concentration afteradministration. For C_(av) and t_(lag) of the Reference formulationmerely the first dosing interval (0-12 h) was considered. Further, theblood plasma concentration profile of the metabolites asenapineglucuronide and N-desmethyl-asenapine was depicted as geometric meanvalues and indicating the geometric mean multiplied with and divided bythe geometric standard deviation as error bars in FIGS. 13c, 13d and 13e.

The biometrical evaluation was carried out using SAS software, Version9.3 of the SAS System for windows. Pharmacokinetics calculations werecarried out using Phoenix WinNonlin version 6.4 The pharmacokineticcalculation was based on all subjects who completed at least 2 treatmentperiods, i.e., who have evaluable data for the Reference and at leastone of Examples 13a or 13b for asenapine and N-desmethyl-asenapine.Thus, the subject number was n=15 for Periods 1 and 2 (Reference andExample 13a) and n=14 for Period 3 (Example 13b). Forasenapine-glucuronide, the subject number was n=8 for all Periods.Values below LLOQ were excluded from any calculations for descriptivestatistics. Descriptive statistics of concentrations were calculated ifat least ½ of the individual data points were measured equal or aboveLLOQ.

Calculation of the pharmacokinetic characteristics were based on actualblood sampling times [h] (relative to the corresponding administrationtime−accepted deviations from planned blood sampling times were within3.5%) rounded to 2 decimal digits and negative pre dose times set tozero.

At time points in the lag time between time zero and the firstquantifiable concentration, concentrations below LLOQ were calculated aszero. Concentrations below LLOQ between 2 quantifiable concentrationswere calculated with half the LLOQ. Trailing concentrations below LLOQwere not used in calculations.

Descriptive statistics of pharmacokinetic parameters were calculatedseparately for each of the Periods 1, 2 and 3. For t_(max), frequencytables were drawn by treatment based on the nominal time of t_(max).

For each of Reference and Examples 13a and 13b, pharmacokineticparameters of asenapine and metabolites were compared by means of anexploratory analysis of variance (ANOVA) model. Arithmetic and geometricmeans used for the calculation of point estimators such as differencesor ratios between treatments were derived from the ANOVA as least squaremeans (LSMEANS) or exponential transformed LSMEANS, respectively. Theinclusion of a 90% confidence interval implies a value of α=0.05 for thetype-I error. No α-adjustment was performed.

Based on fundamental pharmacokinetic relationships, the multiplicativemodel was applied for all concentration related parameters. This impliedthat these characteristics were rather log normally than normallydistributed. The ANOVA, therefore, was performed after logarithmictransformation. Exemplary results are shown in Tables 14.6 and 7.

The plasma concentration profile of asenapine shows that therapeuticconcentrations may be maintained over the entire wearing period of theTTS without major fluctuations. Compared to sublingual administration,maximum concentrations were lower and reached later after transdermalapplication. The formation of the major metabolites,N-desmethyl-asenapine and asenapine-glucuronide, is markedly reducedcompared to sublingual administration.

TABLE 14.3 Descriptive statistics: geometric means and standarddeviation factors of asenapine blood plasma concentration [ng/ml]Reference Ex. 13a Ex. 13b (n = 15) (n = 15) (n = 14) Time [h] Mean SDMean SD Mean SD 0.5 2.32 2.11 — — — — 1 3.21 1.72 — — — — 2 2.9 1.47 — —— — 4 2.64 1.52 0.451 2.78 0.337 2.41 6 — — 0.65 2.45 0.703 1.81 8 1.371.55 1.28 2.08 1.25 1.68 12 0.683 1.57 1.92 1.61 1.76 1.46 12.5 3.211.78 — — — — 13 3.52 1.85 — — — — 14 2.88 1.7  — — — — 16 2.18 1.65 2.271.55 1.93 1.61 20 1.44 1.68 — — — — 24 1.12 1.76 2.72 1.49 2.32 1.39 360.35 1.57 1.71 1.44 1.51 1.28 48 0.273 1.64 2.03 1.33 1.75 1.3  60 0.1821.59 1.41 1.27 1.28 1.25 72 0.183 1.63 1.62 1.28 1.37 1.31 84 — — 1.181.22 1.06 1.28 86 — — 1.17 1.22 1 1.24 88 — — 1.02 1.2  0.862 1.25 96 —— 0.776 1.24 0.665 1.24 108 — — 0.401 1.27 0.352 1.2  120 — — 0.35 1.350.291 1.28 132 — — 0.223 1.31 0.188 1.26 144 — — 0.194 1.33 0.163 1.31156 — — 0.144 1.23 0.129 1.23 168 — — 0.148 1.26 0.132 1.21 Keypharmacokinetic characteristics of Asenapine in plasma Reference Ex. 13aEx. 13b (n = 15) (n = 15) (n = 14) AUC₍₀₋₂₄₎ * 47.4 (1.51) 38.6 (1.61)35.6 (1.46) [(ng/ml) h] 27.3-89.6 22.3-77.5 19.7-72.8 AUC₍₂₄₋₄₈₎ * 12.6(1.66) 49.2 (1.41) 42.7 (1.31) [(ng/ml) h 5.61-28.3 27.5-86.8 31.0-67.6AUC₍₄₈₋₇₂₎ * — 39.0 (1.28) 34.1 (1.27) [(ng/ml) h] 24.5-60.7 22.2-51.7AUC₍₀₋₄₈₎ * 88.2 (1.49) 78.6 (1.36) [(ng/ml) h] 49.7-161  51.8-140 AUC₍₀₋₇₂₎ * 128 (1.42) 113 (1.33) [(ng/ml) h] 74.2-222  80.3-192 AUC₍₀₋₈₄₎ * — 145 (1.39) 128 (1.32) [(ng/ml) h] 85.5-245  89.4-215 C_(max) [ng/ml] * 3.47 (1.61) 2.72 (1.49) 2.37 (1.41) 1.43-6.881.46-5.08 1.56-4.78 C₄₈ [ng/ml] — 2.03 (1.33) 1.75 (1.30) 1.27-3.471.10-2.65 C₇₂ [ng/ml] — 1.62 (1.28) 1.37 (1.31) 1.01-2.26 0.822-2.13 C₈₄ [ng/ml] — 1.18 (1.22) 1.06 (1.28) 0.826-1.61  0.675-1.70  C_(av)[ng/ml] * 1.92 (1.52) 1.72 (1.39) 1.52 (1.32) 0.796-3.34  1.02-2.921.06-2.56 t_(max) [h] ** 1.03 24.0 24.0 0.5-4.0 24.0-24.0 16.0-24.1t_(lag) [h] ** 0.5   4.0  4.0 0.5-1.1 2.0-6.0 2.0-4.0 t_(1/2 λz) [h] *16.5 (1.85) 28.0 (1.38) 27.1 (1.41) 8.18-55.5 16.0-42.7 17.5-52.7 * AUC,C_(max), C_(av) and t_(1/2 λz) given as geometric mean (Standarddeviation), Minimum-Maximum; Standard deviation (SD) given is thegeometric standard deviation factor for both, the descriptive statisticsand key PK characteristics. ** t_(max) and t_(lag) as Median(Minimum-Maximum)

TABLE 14.4 Key pharmacokinetic characteristics of asenapine-glucuronidein plasma Reference Ex. 13a Ex. 13b (n = 8) (n = 8) (n = 8) AUC₍₀₋₂₄₎ * 221 (1.41) 44.0 (1.68) 42.6 (1.69) [(ng/ml) h] 147-383 22.8-115 23.0-116  AUC₍₂₄₋₄₈₎ * 84.4 (1.35) 92.7 (1.52) 76.6 (1.49) [(ng/ml) h]51.8-131  64.0-226  54.4-166  AUC₍₀₋₄₈₎ * —  137 (1.56)  120 (1.55)[(ng/ml) h] 87.6-340  77.4-281  AUC₍₀₋₇₂₎ * —  220 (1.50)  185 (1.50)[(ng/ml) h] 152-521 134-418 AUC₍₀₋₈₄₎ * —  259 (1.48)  214 (1.49)[(ng/ml) h] 183-593 158-478 C_(max) [ng/ml] * 13.4 (1.56) 4.66 (1.54)3.84 (1.45) 7.75-28.0 3.05-11.1 2.68-7.71 t_(max) [h] ** 4.00 36.0 36.04.00-4.05 36.0-83.9 36.0-60.0 t_(lag) [h] ** 1.00 6.01 6.00 1.00-1.034.00-8.00 4.00-8.02 t_(1/2 λz) [h] * 15.9 (1.47) 27.9 (1.38) 21.6 (1.24)8.12-29.2 17.3-50.0 14.4-27.4 * AUC, C_(max) and t_(1/2 λz) given asgeometric mean (Standard deviation), Minimum − Maximum; Standarddeviation given is the geometric standard deviation factor ** t_(max)and t_(lag) as Median (Minimum − Maximum)

TABLE 14.5 Key pharmacokinetic characteristics of N-desmethyl-asenapinein plasma Reference Ex. 13a Ex. 13b (n = 15) (n = 15) (n = 14)AUC₍₀₋₂₄₎ * 11.5 (1.42) 1.67 (2.43) 1.27 (2.16) [(ng/ml) h] 6.34-20.10.452-5.79  0.420-3.87  AUC₍₀₋₄₈₎ * — 9.10 (1.69) 7.51 (1.54) [(ng/ml)h] 4.27-24.1 3.97-16.2 AUC₍₀₋₇₂₎ * — 16.8 (1.62) 14.4 (1.51) [(ng/ml) h]8.27-42.9 7.79-30.8 AUC₍₀₋₈₄₎ * — 20.3 (1.59) 17.5 (1.50) [(ng/ml) h]10.1-51.5 9.31-38.0 C_(max) [ng/ml] * 0.514 (1.43)  0.351 (1.58)  0.310(1.49)  0.259-0.969 0.173-0.846 0.165-0.634 t_(max) [h] ** 8.00 48.060.0 4.00-11.9 36.0-84.1 36.0-72.0 t_(lag) ** 2.02 16.0 16.0 1.00-4.058.00-24.0 12.0-24.1 * AUC and C_(max) given as geometric mean (Standarddeviation), Minimum − Maximum; Standard deviation given is the geometricstandard deviation factor ** t_(max) and t_(lag) as Median (Minimum −Maximum)

TABLE 14.6 90% confidence intervals for log transformed pharmacokineticcharacteristics of asenapine-glucuronide Point Lower Upper estimatelimit of 90% limit of 90% Comparison (%) CI (%) CI (%) AUC ₍₀₋₄₈₎ Period2/Reference 44.70 37.04 53.93 Period 3/Reference 39.04 32.35 47.10Period 2/Period 3 114.49 94.90 138.14 C_(max) Period 2/Reference 34.8727.01 45.03 Period 3/Reference 28.74 22.26 37.11 Period 2/Period 3121.34 93.97 156.70

TABLE 14.7 90% confidence intervals for log transformed pharmacokineticcharacteristics of N-desmethyl-asenapine Point Lower Upper estimatelimit of limit of Comparison (%) 90% CI (%) 90% CI (%) AUC ₍₀₋₄₈₎ Period2/Reference 41.47 34.95 49.21 Period 3/Reference 33.13 27.80 39.47Period 2/Period 3 125.18 105.05 149.17 C_(max) Period 2/Reference 68.3458.52 79.80 Period 3/Reference 58.77 50.14 68.90 Period 2/Period 3116.28 99.19 136.31Adverse Events (AE)

Tables 14.8 and 14.9 reflect the number of adverse events reported inthe different categories.

Although treatment duration for the sublingual tablet (Reference) wasonly 12 h (i.e., 2 administrations) compared to 3.5 days TTS application(Examples 13a and 13b), common systemic side effects of asenapinetreatment, such as fatigue and dizziness, were observed less frequentlyafter TTS application and, in case of fatigue, only with mild intensity.In comparison to the sublingually administered treatment (Reference),the frequency and intensity of fatigue was notably lower aftertransdermal administration, and dizziness occurred with lower frequency.

Oral discomfort symptoms, such as hypoaesthesia and dry mouth, asobserved following the administration of the reference treatment, werenot observed under TTS application (Examples 13a and 13b).

Local tolerance at the application site was good, only mild reactionswere observed occasionally (five AEs) which subsided withoutintervention.

The dysmenorrhea reported during period 3, which was moderate inintensity, had no relationship to the TS of Example 13b administered.

No SAE was reported and none of the subjects had suicidal ideations.

Overall, transdermal application of asenapine was safe and welltolerated. The AEs observed after administration of either TIS (Periods2 and 3) were mostly mild and transient, resolved without intervention,and the frequency of AEs was lower compared to the reference period 1.

TABLE 14.8 Adverse events (AE) and serious adverse events (SAE) reportedduring the study Period 1 Period 2 Period 3 (Reference) (Example 13a)(Example 13b) (n = 16) (n = 15) (n = 15) total Mild (AE) 41 26 17 84Moderate (AE) 13 1 2 16 Sever AE) 3 0 1 4 Serious (SAE) 0 0 0 0 total 5727 20 104 Outcome: Number of 57 27 20 104 subjects recovered

TABLE 14.9 Adverse events (AE) by type of AE Period 2 Period 3 Period 1(Example (Example (Reference) 13a) 13b) (n = 16) (n = 15) (n = 15) totalFatigue* 21 12 11 44 (8/11/2) (11/1/0) (10/1/0) Dizziness 11 7 2 15Flypoaesthesia oral 12 0 0 12 Gastrointestinal disorders 5 1 0 6(Abdominal pain upper, constipation, diarrhoea, dry mouth) Other generaldisorders 1 6 2 9 and administration site conditions Musculoskeletal and1 0 0 connective tissue disorders pain in extremity) Other nervoussystem 6 6 4 16 disorders (akathisia, head discomfort, headache,paraesthesia, presyncope) Dysmenorrhoea 0 0 1 1 total 57 27 20 104*Numbers in parentheses indicate incidences by intensity(mild/moderate/severe

The invention relates in particular to the following further items:

1. Transdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containing atherapeutically effective amount of asenapine, said self-adhesive layerstructure comprising:

-   -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine; and        -   2. a polymer selected from acrylic polymers;            wherein the transdermal therapeutic system has an area of            release of from 5 to 100 cm².            2. Transdermal therapeutic system according to item 1,            wherein the transdermal therapeutic system contains at least            0.70 mg/cm², preferably at least 0.80 mg-cm², more            preferably at least 0.82 mg/cm² and most preferably at least            0.83 mg/cm² asenapine.            3. Transdermal therapeutic system according to item 1 or 2,            wherein the transdermal therapeutic system contains from            0.70 mg/cm² to 4.0 mg/cm², preferably from 0.80 mg/cm² to            3.0 mg/cm², more preferably from 0.82 mg/cm² to 2.0 mg/cm²            and most preferably from 0.83 mg/cm² to 1.7 mg/cm²            asenapine.            4. Transdermal therapeutic system according to any one of            items 1 to 3.            wherein the area weight of the matrix layer ranges from 90            to 230 g/m², preferably from 110 to 210 g/m², and most            preferably from 120 to 170 g/m².            5. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 0.5 to 20 mg/day            over at least 48 hours of administration.            6. Transdermal therapeutic system according to item 5,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 0.5 to 20 mg/day            over at least 72 hours, preferably over 84 hours of            administration.            7. Transdermal therapeutic system according to item 5 or 6,            wherein the transdermal therapeutic system provides by            transdermal deliver) a mean release rate of 1.0 to 15            mg/day, preferably of 2.0 to 10 mg/day over at least 48            hours of administration, or            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 1.0 to 15            mg/day, preferably of 2.0 to 10 mg/day over at least 72            hours of administration, or            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 1.0 to 15            mg/day, preferably of 2.0 to 10 mg/day over 84 hours of            administration.            8. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery an AUC₀₋₄₈ from 20 to 300 (ng/ml) h or            from more than 300 to 450 (ng/ml) h.            9. Transdermal therapeutic system according to item 8,            wherein the transdermal therapeutic system provides by            transdermal deliver an AUC₀₋₄₈ from 30 to 200 (ng/ml) h.            10. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery an AUC₀₋₇₂ from 30 to 400 (ng/ml) h or            from more than 400 to 600 (ng/ml) h.            11. Transdermal therapeutic system according to item 10,            wherein the transdermal therapeutic system provides by            transdermal delivery an AUC₀₋₇₂ from 50 to 300 (ng/ml) h.            12. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery an AUC₀₋₈₄ from 35 to 450 (ng/ml) h or            from more than 450 to 700 (ng/ml) h.            13. Transdermal therapeutic system according to item 12,            wherein the transdermal therapeutic system provides by            transdermal delivery an AUC₀₋₈₄ from 60 to 350 (ng/ml) h.            14. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery a C_(max) to C₄₈ ratio of less than            2.0.            15. Transdermal therapeutic system according to item 14,            wherein the transdermal therapeutic system provides by            transdermal delivery a C_(max) to C₄₈ ratio of less than 1.5            and preferably of less than 1.3.            16. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery a C_(max) to C₇₂ ratio of less than            3.0.            17. Transdermal therapeutic system according to item 16,            wherein the transdermal therapeutic system provides by            transdermal delivery a C_(max) to C₇₂ ratio of less than 2.5            and preferably of less than 2.0.            18. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery a C_(max) to C₈₄ ratio of less than            3.5.            19. Transdermal therapeutic system according to item 18,            wherein the transdermal therapeutic system provides by            transdermal delivery a C_(max) to C₈₄ ratio of less than            3.0, preferably of less than 2.5 and more preferably of less            than 2.0.            20. Transdermal therapeutic system according to any one of            items 5 to 19, comprising a self-adhesive layer structure            containing a therapeutically effective amount of asenapine,            said self-adhesive layer structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine; and        -   2. a polymer.            21. Transdermal therapeutic system according to any one of            items 1 to 4 and 20, wherein the asenapine-containing matrix            layer does not comprise isopropyl palmitate in an amount of            10% of the matrix layer composition, preferably does not            comprise isopropyl palmitate in an amount of 5-15% of the            matrix layer composition and most preferably does not            comprise isopropyl palmitate.            22. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing a therapeutically effective amount of            asenapine, said self-adhesive layer structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine in the form of the free base; and        -   2. a polymer;            wherein the area weight of the matrix layer is at least 90            g/m², and            wherein the asenapine-containing matrix layer does not            comprise isopropyl palmitate.            23. Transdermal therapeutic system according to any one of            items 5 to 22,            wherein the transdermal therapeutic system contains at least            0.70 mg/cm², preferably at least 0.80 mg/cm², more            preferably at least 0.82 mg/cm² and most preferably at least            0.83 mg/cm² asenapine.            24. Transdermal therapeutic system according to any one of            items 5 to 23,            wherein the transdermal therapeutic system contains from            0.70 mg/cm² to 4.0 mg/cm², preferably from 0.80 mg/cm² to            3.0 mg/cm², more preferably from 0.82 mg/cm² to 2.0 mg/cm²            and most preferably from 0.83 mg/cm² to 1.7 mg/cm²            asenapine.            25. Transdermal therapeutic system according to any one of            items 5 to 24,            wherein the area weight of the matrix layer ranges from 90            to 230 g/m², preferably from 110 to 210 g/m², and most            preferably from 120 to 170 g/m².            26. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 25,            wherein the matrix layer composition does not comprise any            of polysiloxanes and polyisobutylenes in an amount of more            than 50% of the matrix layer composition.            27. Transdermal therapeutic system according to any one of            items 20 to 26,            wherein the polymer is selected from polysiloxanes,            polyisobutylenes, styrene-isoprene-styrene block copolymers            and acrylic polymers.            28. Transdermal therapeutic system according to any one of            items 20 to 26,            wherein the polymer is selected from acrylic polymers.            29. Transdermal therapeutic system according to any one of            items 5 to 28,            wherein the transdermal therapeutic system has an area of            release of from 5 to 100 cm².            30. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 29,            wherein the asenapine-containing matrix layer does not            comprise isopropyl myristate in an amount of 5% of the            matrix layer composition, preferably does not comprise            isopropyl myristate in an amount of 1-10% of the matrix            layer composition and most preferably does not comprise            isopropyl myristate.            31. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 30,            wherein the asenapine-containing matrix layer does not            comprise ethyl cellulose in an amount of 10-20% of the            matrix layer composition and preferably does not comprise            ethyl cellulose.            32. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 31,            wherein the asenapine-containing matrix layer does not            comprise hydrogen chloride.            33. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 32,            wherein the asenapine-containing matrix layer does not            comprise toluene.            34. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 33,            wherein the asenapine-containing matrix layer is obtainable            by drying a coated coating composition wherein no            hydrochloric acid has been included in the coating            composition.            35. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 34,            wherein the asenapine-containing matrix layer is obtainable            by drying a coated coating composition comprising no            toluene.            36. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 35,            wherein the asenapine in the matrix layer composition is            included in the form of the free base.            37. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 36,            wherein the matrix layer composition is obtainable by            incorporating the asenapine in the form of the free base.            38. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 37,            wherein at least 90 mol %, preferably at least 95 mol %,            more preferably at least 98 mol % and most preferably at            least 99 mol % of the asenapine in the matrix layer is            present in the form of the free base.            39. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 38,            wherein the asenapine in the matrix layer is completely            dissolved.            40. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 39,            wherein the matrix layer composition contains asenapine            particles, preferably constituted of asenapine free base.            41. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 40,            wherein the amount of asenapine in the matrix layer            composition ranges from 2 to 20%, preferably from 3 to 15%            and more preferably from 4 to 12% of the matrix layer            composition.            42. Transdermal therapeutic system according to any one of            items 1 to 41,            wherein the asenapine has a purity of at least 95%,            preferably of at least 98% and more preferably of at least            99% as determined by quantitative HPLC.            43. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 42,            wherein the matrix layer composition is a pressure-sensitive            adhesive composition.            44. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 43,            wherein the polymer is selected from pressure-sensitive            adhesive polymers.            45. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 44,            wherein the polymer is selected from acrylic polymers            comprising functional groups.            46. Transdermal therapeutic system according to item 45,            wherein the functional groups are selected from hydroxyl            groups, carboxylic acid groups, neutralized carboxylic acid            groups and mixtures thereof.            47. Transdermal therapeutic system according to item 46,            wherein the functional groups are limited to hydroxyl            groups.            48. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 47,            wherein the polymer is selected from acrylic polymers which            do not comprise carboxylic acid groups or neutralized            carboxylic acid groups or both groups.            49. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 48,            wherein the polymer is selected from acrylic polymers which            do not comprise acidic groups.            50. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 49,            wherein the polymer is selected from acrylic polymers            comprising hydroxyl groups and no carboxylic acid groups.            51. Transdermal therapeutic system according to item 50,            wherein the polymer is a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate.            52. Transdermal therapeutic system according to item 51,            wherein the polymer is cross-linked by a cross-linking agent            and preferably is cross-linked by a titanium cross-linking            agent.            53. Transdermal therapeutic system according to item 51,            wherein the polymer is not cross-linked by a cross-linking            agent.            54. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 44,            wherein the polymer is selected from acrylic polymers            comprising no hydroxyl groups and no carboxylic acid groups.            55. Transdermal therapeutic system according to item 54,            wherein the polymer is selected from acrylic polymers            comprising no functional groups.            56. Transdermal therapeutic system according to item 55,            wherein the polymer is a copolymer based on methyl acrylate,            2-ethylhexyl acrylate and t-octyl acrylamide, or a copolymer            based on 2-ethylhexyl-acrylate and vinyl acetate.            57. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 56,            wherein the amount of the polymer ranges from 60 to 97%,            preferably from 70 to 96% and more preferably from 75 to 88%            or from 91 to 96% of the matrix layer composition.            58. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 57,            wherein the total polymer content in the matrix layer            composition ranges from 75 to 97%, preferably from 80 to 96%            and more preferably from 85 to 95% of the matrix layer            composition.            59. Transdermal therapeutic system according to any one of            items 1 to 58,            wherein the transdermal therapeutic system has an area of            release of from 5 to 100 cm², preferably from 10 to 80 cm²,            and more preferably from 10 to 20 cm², from 25 to 35 cm² and            55 to 65 cm².            60. Transdermal therapeutic system according to any one of            items 1 to 59,            wherein the amount of asenapine contained in the transdermal            therapeutic system ranges from 5 to 100 mg, preferably from            10 to 80 mg, and most preferably from 15 to 60 mg.            61. Transdermal therapeutic system according to any one of            items 1 to 60,            wherein the transdermal therapeutic system has an area of            release of from 5 to 100 cm², and the amount of asenapine            contained in the transdermal therapeutic system ranges from            5 to 100 mg.            62. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 61,            wherein the matrix layer composition comprises further            excipients or additives selected from the group consisting            of cross-linking agents, solubilizers, fillers, tackifiers,            plasticizers, stabilizers, softeners, substances for            skincare, permeation enhancers, pH regulators, and            preservatives.            63. Transdermal therapeutic system according to item 62,            wherein the tackifier is selected from polyvinylpyrrolidone,            triglycerides, dipropylene glycol, resins, resin esters,            terpenes and derivatives thereof, ethylene vinyl acetate            adhesives, dimethylpolysiloxanes and polybutenes, preferably            polyvinylpyrrolidone and more preferably soluble            polyvinylpyrrolidone.            64. Transdermal therapeutic system according to item 62,            wherein the stabilizer is selected from sodium            metabisulfite, ascorbic acid and ester derivatives thereof,            butylated hydroxytoluene, tocopherol and ester derivatives            thereof such as tocopheryl acetate and tocopheryl linoleate,            as well as a combination of tocopherol and ascorbyl            palmitate, preferably from tocopherol and ester derivatives            thereof and ascorbic acid and ester derivatives thereof, and            is more preferably selected from ascorbyl esters of fatty            acids and tocopherol, and most preferably is ascorbyl            palmitate or α-tocopherol or a combination thereof.            65. Transdermal therapeutic system according to item 62,            wherein the permeation enhancer is selected from diethylene            glycol monoethyl ether, diisopropyl adipate, isopropyl            myristate, isopropyl palmitate, lauryl lactate,            dimethylpropylene urea and a mixture of propylene glycol            monoesters and diesters of fatty acids.            66. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 65,            wherein the matrix layer composition does not comprise a            permeation enhancer selected from oleic acids,            triglycerides, oleic alcohols, and mixtures thereof.            67. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 66,            wherein the matrix layer composition does not comprise a            permeation enhancer.            68. Transdermal therapeutic system according to any one of            items 1 to 4 and 20 to 67,            wherein the matrix layer composition further comprises a            copolymer based on dimethylaminoethyl methacrylate, butyl            methacrylate and methyl methacrylate.            69. Transdermal therapeutic system according to any one of            items 1 to 68,            wherein the transdermal therapeutic system provides a mean            release rate of 0.5 to 20 mg/day, preferably of 1.0 to 15            mg/day, and more preferably of 2.0 to 10 mg/day over at            least 24 hours of administration, preferably over at least            48 hours of administration, more preferably over at least 72            hours of administration.            70. Transdermal therapeutic system according to any one of            items 1 to 69,            providing a cumulative skin permeation rate of asenapine at            hour 48 or at hour 72 as measured in a Franz diffusion cell            with dermatomed human skin of 1 μg/(cm² h) to 20 μg/(cm² h),            preferably of 2 μg/(cm² h) to 15 μg/(cm² h) and more            preferably of 4 μg/(cm² h) to 12 μg/(cm² h).            71. Transdermal therapeutic system according to any one of            items 1 to 70,            providing a skin permeation rate of asenapine as measured in            a Franz diffusion cell with dermatomed human skin of

0 μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours,

2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 24 to hour 32,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour 48,

2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour 72.

72. Transdermal therapeutic system according to any one of items 1 to71,

providing a cumulative permeated amount of asenapine as measured in aFranz diffusion cell with dermatomed human skin of 0.05 mg/cm² to 1.0mg/cm², preferably of 0.1 mg/cm² to 0.7 mg/cm² over a time period of 48hours.

73. Transdermal therapeutic system according to any one of items 1 to72,

providing a cumulative permeated amount of asenapine as measured in aFranz diffusion cell with dermatomed human skin of 0.1 mg/cm² to 2.0mg/cm², preferably 0.2 mg/cm² to 1.0 mg/cm² over a time period of 72hours.

74. Transdermal therapeutic system according to any one of items 1 to73, further comprising a release liner.

75. Transdermal therapeutic system according to any one of items 1 to74, further comprising an adhesive overlay or comprising no adhesiveoverlay, and preferably comprising no adhesive overlay.

76. Transdermal therapeutic system according to any one of items 1 to75,

wherein the backing layer is substantially asenapine-impermeable.

77. Transdermal therapeutic system according to any one of items 1 to76,

wherein the self-adhesive layer structure does not comprise anadditional skin contact layer.

78. Transdermal therapeutic system according to any one of items 1 to76,

wherein the self-adhesive layer structure comprises an additional skincontact layer.

79. Transdermal therapeutic system according to item 78,

wherein the self-adhesive layer structure comprises a membrane which islocated between the matrix layer and the additional skin contact layer,wherein the membrane is preferably a rate controlling membrane.

80. Transdermal therapeutic system according to any one of items 1 to79,

wherein the self-adhesive layer structure comprises an additionalreservoir layer which is located between the backing layer and thematrix layer, and a further rate controlling membrane which is locatedbetween the additional reservoir layer and the matrix layer.81. Transdermal therapeutic system according to any one of items 1 to80,wherein the transdermal therapeutic system is a matrix-type TTS.82. Transdermal therapeutic system according to any one of items 1 to 81for use in a method of treatment, preferably for use in a method oftreating psychosis and more preferably for use in a method of treatingone or more conditions selected from schizophrenia, bipolar disorder,posttraumatic stress disorder, major depressive disorder, dementiarelated psychosis, agitation and manic disorder.83. Transdermal therapeutic system according to item 82for use in a method of treating schizophrenia and/or bipolar disorder.84. Transdermal therapeutic system according to item 82for use in a method of treating bipolar disorder, in particular acutemanic or mixed episodes of bipolar disorder.85. Transdermal therapeutic system according to any one of items 82 to84for use in a method of treatment with a dosing interval of at least 24hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or 3days.86. Transdermal therapeutic system according to any one of items 82 to85for use in a method of treatment with a dosing interval of up to 168hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days.87. Transdermal therapeutic system according to item 85for use in a method of treatment with a dosing interval of 24 hours or 1day.88. Transdermal therapeutic system according to item 85for use in a method of treatment with a dosing interval of 48 hours or 2days.89. Transdermal therapeutic system according to item 85for use in a method of treatment with a dosing interval of 84 hours or3.5 days.90. Transdermal therapeutic system according to any one of items 82 to89for use in a method of treating a patient,

-   -   wherein the transdermal therapeutic system provides a reduction        in at least one asenapine-related side effect relative to an        equivalent dose of sublingual asenapine.        91. Transdermal therapeutic system according to item 90 for use        in a method of treating a patient, wherein

the patient is a human patient suffering from fatigue, somnolence,dizziness, or any combination thereof, or

the at least one asenapine-related side effect is fatigue, somnolence,dizziness, oral hypoaesthesia, or any combination thereof, or

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness, and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

92. Transdermal therapeutic system according to any one of items 1 to 81for use in a method of reducing, in a patient, at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine.

93. Transdermal therapeutic system according to item 92 for use in amethod of reducing, in a patient, at least one asenapine-related sideeffect relative to an equivalent dose of sublingual asenapine, wherein

the patient is a human patient suffering from fatigue, somnolence,dizziness, or any combination thereof, or

the at least one asenapine-related side effect is fatigue, somnolence,dizziness, oral hypoaesthesia, or any combination thereof, or

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

94. A method of treatment, and in particular a method of treatingpsychosis and more preferably a method of treating one or moreconditions selected from schizophrenia, bipolar disorder, posttraumaticstress disorder, major depressive disorder, dementia related psychosis,agitation and manic disorderincluding applying a transdermal therapeutic system according to any oneof items 1 to 81 to the skin of a patient.95. A method of treating schizophrenia and/or bipolar disorderincluding applying a transdermal therapeutic system according to any oneof items 1 to 81 to the skin of a patient.96. A method of treating bipolar disorder and in particular acute manicor mixed episodes of bipolar disorderincluding applying a transdermal therapeutic system according to any oneof items 1 to 81 to the skin of a patient.97. A method of treatment according to any one of items 94 to 96including applying a transdermal therapeutic system according to any oneof items 1 to 81 for at least 24 hours or 1 day, at least 48 hours or 2days, or at least 72 hours or 3 days to the skin of a patient.98. A method of treatment according to any one of items 94 to 96including applying a transdermal therapeutic system according to any oneof items 1 to 81 for up to 168 hours or 7 days, up to 120 hours or 5days, or up to 96 hours or 4 days to the skin of a patient.99. A method of treatment according to any one of items 94 to 96including applying a transdermal therapeutic system according to any oneof items 1 to 81 for 24 hours or 1 day to the skin of a patient.100. A method of treatment according to any one of items 94 to 96including applying a transdermal therapeutic system according to any oneof items 1 to 81 for 48 hours or 2 days to the skin of a patient.101. A method of treatment according to any one of items 94 to 96including applying a transdermal therapeutic system according to any oneof items 1 to 81 for 84 hours or 3.5 days to the skin of a patient.102. The method of treatment according to any one of items 94 to 101wherein the transdermal therapeutic system provides a reduction in atleast one asenapine-related side effect relative to an equivalent doseof sublingual asenapine.103. The method of treatment according to item 102,wherein the patient is a human patient suffering from fatigue,somnolence, dizziness, or any combination thereof.104. The method of treatment according to item 102 or 103,wherein the at least one asenapine-related side effect is fatigue,somnolence, dizziness, oral hypoaesthesia, or any combination thereof.105. The method of treatment according to any one of items 102 to 104wherein the incidence of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced by atleast about 30%, at least about 40%, at least about 70% or at leastabout 80%, and/or wherein the intensity of the at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine is reduced.106. The method of treatment according to item 105, wherein

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40%, and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

107. A method of reducing, in a patient, at least one asenapine-relatedside effect relative to an equivalent dose of sublingual asenapine, themethod comprising administering a transdermal therapeutic systemaccording to any one of items 1 to 81.

108. The method according to item 107,

wherein the patient is a human patient suffering from fatigue,somnolence, dizziness, or any combination thereof.

109. The method according to item 107 or 108,

wherein the at least one asenapine-related side effect is fatigue,somnolence, dizziness, oral hypoaesthesia, or any combination thereof.

110. The method according to any one of items 107 to 109

wherein the incidence of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced by atleast about 30%, at least about 40%, at least about 70% or at leastabout 80%, and/or wherein the intensity of the at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine is reduced.111. The method according to item 110, wherein

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

112. A method of reducing at least one asenapine-related side effect ina patient being treated with sublingual asenapine therapy, the methodcomprising:

-   -   a) discontinuing sublingual asenapine therapy; and    -   b) administering a transdermal therapeutic system according to        any of items 1 to 81 to the skin of the patient, wherein the        transdermal therapeutic system provides a reduction in at least        one asenapine-related side effect relative to an equivalent dose        of sublingual asenapine.        113. The method of item 112, wherein the transdermal therapeutic        system delivers an amount of asenapenaine equivalent to the        amount of asenapine originally provided by the sublingual        asenapine therapy.        114. Asenapine for use in a method of treating a human patient        by transdermal administration of asenapine for a dosing interval        of at least 48 hours or 2 days.        115. Asenapine for use in a method of treating a human patient        by transdermal administration of asenapine for a dosing interval        of at least 72 hours or 3 days.        116. Asenapine for use in a method of treating a human patient        according to item 114 or 115 wherein the dosing interval is up        to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96        hours or 4 days.        117. Asenapine for use in a method of treating a human patient        according to item 114 or 115, wherein the dosing interval is 48        hours or 2 days, or 72 hours or 3 days, or 84 hours or 3.5 days.        118. Asenapine for use in a method of treating a human patient        according to any one of items 114 to 117,        for use in a method of treating psychosis, and in particular for        use in a method of treating one or more conditions selected from        schizophrenia, bipolar disorder, posttraumatic stress disorder,        major depressive disorder, dementia related psychosis, agitation        and manic disorder, or for use in a method of treating        schizophrenia and/or bipolar disorder, preferably bipolar        disorder and in particular acute manic or mixed episodes of        bipolar disorder.        119. Asenapine for use in a method of treating a human patient        according to any one of items 114 to 118        providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0        to 10 mg/day over at least 48 hours or 2 days of administration,        or        providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0        to 10 mg/day over at least 72 hours or 3 days of administration,        or        providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0        to 10 mg/day over at least 84 hours or 3.5 days of        administration.        120. Asenapine for use in a method of treating a human patient        according to any one of items 114 to 119        providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300        (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably        from 30 to 200 (ng/ml) h, or        providing by transdermal delivery an AUC₀₋₇₂ from 30 to 400        (ng/ml) h or from more than 400 to 600 (ng/ml) h and preferably        from 50 to 300 (ng/ml) h, or        providing by transdermal delivery an AUC₀₋₈₄ from 35 to 450        (ng/ml) h or from more than 450 to 700 (ng/ml) h and preferably        from 60 to 350 (ng/ml) h.        121. Asenapine for use in a method of treating a human patient        according to any one of items 114 to 120        providing by transdermal delivery a C_(max) to C₄₈ ratio of less        than 2.0, preferably of less than 1.5 and more preferably of        less than 1.3, or        providing by transdermal delivery a C_(max) to C₇₂ ratio of less        than 3.0, preferably of less than 2.5 and more preferably of        less than 2.0, or        providing by transdermal delivery a C_(max) to C₈₄ ratio of less        than 3.5, preferably of less than 3.0, more preferably of less        than 2.5 and most preferably of less than 2.0.        122. Asenapine for use in a method of treating a human patient        according to any one of items 114 to 121        wherein at least one asenapine-related side effect relative to        an equivalent dose of sublingual asenapine is reduced.        123. Asenapine for use in a method of treating a human patient        according to item 122, wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, or

the at least one asenapine-related side effect is fatigue, somnolence,dizziness, oral hypoaesthesia, or any combination thereof, or

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

124. Transdermal therapeutic system for the transdermal administrationof asenapine for use in a method of treating a human patient for adosing interval of at least 48 hours or 2 days.

125. Transdermal therapeutic system for the transdermal administrationof asenapine for use in a method of treating a human patient for adosing interval of at least 72 hours or 3 days.

126. Transdermal therapeutic system for use in a method of treating ahuman patient according to item 124 or 125

wherein the dosing interval is up to 168 hours or 7 days, up to 120hours or 5 days, or up to 96 hours or 4 days.

127. Transdermal therapeutic system for use in a method of treating ahuman patient according to item 124 or 125

wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3days, or 84 hours or 3.5 days.

128. Transdermal therapeutic system for use in a method of treating ahuman patient according to any one of items 124 to 127,

comprising a self-adhesive layer structure containing a therapeuticallyeffective amount of asenapine.

129. Transdermal therapeutic system for use in a method of treating ahuman patient according to any one of items 124 to 128

for use in a method of treating psychosis, and in particular for use ina method of treating one or more conditions selected from schizophrenia,bipolar disorder, posttraumatic stress disorder, major depressivedisorder, dementia related psychosis, agitation and manic disorder, orfor use in a method of treating schizophrenia and/or bipolar disorder,preferably bipolar disorder and in particular acute manic or mixedepisodes of bipolar disorder.130. Transdermal therapeutic system for use in a method of treating ahuman patient according to any one of items 124 to 129providing by transdermal delivery a mean release rate of 0.5 to 20mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/dayover at least 48 hours of administration, orproviding by transdermal delivery a mean release rate of 0.5 to 20mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/dayover at least 72 hours of administration, or providing by transdermaldelivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15mg/day, more preferably of 2.0 to 10 mg/day over at least 84 hours ofadministration.131. Transdermal therapeutic system for use in a method of treating ahuman patient according to any one of items 124 to 130providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300 (ng/ml) h orfrom more than 300 to 450 (ng/ml) h and preferably from 30 to 200(ng/ml) h, orproviding by transdermal delivery an AUC₀₋₇₂ from 30 to 400 (ng/ml) h orfrom more than 400 to 600 (ng/ml) h and preferably from 50 to 300(ng/ml) h, orproviding by transdermal delivery an AUC₀₋₈₄ from 35 to 450 (ng/ml) h orfrom more than 450 to 700 (ng/ml) h and preferably from 60 to 350(ng/ml) h.132. Transdermal therapeutic system for use in a method of treating ahuman patient according to any one of items 124 to 131providing by transdermal delivery a C_(max) to C₄₈ ratio of less than2.0, preferably of less than 1.5 and more preferably of less than 1.3,orproviding by transdermal delivery a C_(max) to C₇₂ ratio of less than3.0, preferably of less than 2.5 and more preferably of less than 2.0,orproviding by transdermal delivery a C_(max) to C₈₄ ratio of less than3.5, preferably of less than 3.0, more preferably of less than 2.5 andmost preferably of less than 2.0.133. Transdermal therapeutic system according to any one of items 124 to132 for use in a method of treating a patient,

wherein the transdermal therapeutic system provides a reduction in atleast one asenapine-related side effect relative to an equivalent doseof sublingual asenapine.

134. Transdermal therapeutic system according to item 133 for use in amethod of treating a patient, wherein

the patient is a human patient suffering from fatigue, somnolence,dizziness, or any combination thereof, or

the at least one asenapine-related side effect is fatigue, somnolence,dizziness, oral hypoaesthesia, or any combination thereof, or

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

135. A method of treating a human patient by transdermal administrationof asenapine for a dosing interval of at least 48 hours or 2 days.

136. A method of treating a human patient by transdermal administrationof asenapine for a dosing interval of at least 72 hours or 3 days.

137. The method of treating a human patient by transdermaladministration of asenapine according to item 135 or 136,

wherein the dosing interval is up to 168 hours or 7 days, up to 120hours or 5 days, or up to 96 hours or 4 days.

138. The method of treating a human patient by transdermaladministration of asenapine according to item 135 or 136,

wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3days, or 84 hours or 3.5 days.

139. The method of treating a human patient by transdermaladministration of asenapine according to any one of items 135 to 138,

including applying a transdermal therapeutic system for the transdermaladministration of asenapine for at least 48 hours or 2 days, for atleast 72 hours or 3 days, for 48 hours or 2 days, for 72 hours or 3days, or for 84 hours or 3.5 days to the skin of a patient.140. The method of treating a human patient by transdermaladministration of asenapine according to any one of items 135 to 139,wherein the transdermal therapeutic system for the transdermaladministration of asenapine comprises a self-adhesive layer structurecontaining a therapeutically effective amount of asenapine.141. The method of treating psychosis, and in particular the method oftreating one or more conditions selected from schizophrenia, bipolardisorder, posttraumatic stress disorder, major depressive disorder,dementia related psychosis, agitation and manic disorder, or the methodof treating schizophrenia and/or bipolar disorder according to any oneof items 135 to 140.142. The method of treating schizophrenia and/or bipolar disorder,preferably bipolar disorder and in particular acute manic or mixedepisodes of bipolar disorder according to any one of items 135 to 141.143. The method of treating a human patient according to any one ofitems 135 to 142providing by transdermal delivery a mean release rate of 0.5 to 20mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/dayover at least 48 hours of administration, orproviding by transdermal delivery a mean release rate of 0.5 to 20mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/dayover at least 72 hours of administration, orproviding by transdermal delivery a mean release rate of 0.5 to 20mg/day, preferably 1.0 to 15 mg/day, more preferably of 2.0 to 10 mg/dayover at least 84 hours of administration.144. The method of treating a human patient according to any one ofitems 135 to 143providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300 (ng/ml) h orfrom more than 300 to 450 (ng/ml) h and preferably from 30 to 200(ng/ml) h, orproviding by transdermal delivery an AUC₀₋₇₂ from 30 to 400 (ng/ml) h orfrom more than 400 to 600 (ng/ml) h and preferably from 50 to 300(ng/ml) h, orproviding by transdermal delivery an AUC₀₋₈₄ from 35 to 450 (ng/ml) h orfrom more than 450 to 700 (ng/ml) h and preferably from 60 to 350(ng/ml) h.145. The method of treating a human patient according to any one ofitems 135 to 144providing by transdermal delivery a C_(max) to C₄₈ ratio of less than2.0, preferably of less than 1.5 and more preferably of less than 1.3,orproviding by transdermal delivery a C_(max) to C₇₂ ratio of less than3.0, preferably of less than 2.5 and more preferably of less than 2.0,orproviding by transdermal delivery a C_(max) to C₈₄ ratio of less than3.5, preferably of less than 3.0, more preferably of less than 2.5 andmost preferably of less than 2.0.146. The method of treating a human patient according to any one ofitems 135 to 145 wherein the transdermal therapeutic system provides areduction in at least one asenapine-related side effect relative to anequivalent dose of sublingual asenapine.147. The method of treating a human patient according to item 146,wherein the human patient is suffering from fatigue, somnolence,dizziness, or any combination thereof.148. The method of treating a human patient according to item 146 or147, wherein the at least one asenapine-related side effect is fatigue,somnolence, dizziness, oral hypoaesthesia, or any combination thereof.149. The method of treating a human patient according to any one ofitems 146 to 148 wherein the incidence of the at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine is reduced by at least about 30% at least about40%, at least about 70% or at least about 80%, and/or wherein theintensity of the at least one asenapine-related side effect relative toan equivalent dose of sublingual asenapine is reduced.150. The method of treating a human patient according to item 149,wherein

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% at least about 40% and/or theintensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

151. Transdermal therapeutic system for the transdermal administrationof asenapine for use in a method of treating a human patient, wherein

the transdermal therapeutic system provides a reduction in at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine, and wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

152. Transdermal therapeutic system according to item 151 for use in amethod of treating a human patient, wherein

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

153. A method of treating a human patient by transdermal administrationof asenapine wherein at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced, and wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

154. The method of treating a human patient according to item 153,wherein

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

155. A method of reducing, in a human patient, at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine, the method comprising transdermal administrationof asenapine, wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

156. The method of treating a human patient according to item 155,wherein

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

157. A method of reducing at least one asenapine-related side effect ina patient being treated with sublingual asenapine therapy, the methodcomprising:

a) discontinuing sublingual asenapine therapy; and

b) transdermal administration of asenapine,

wherein the patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

158. The method of item 157, wherein the transdermal therapeutic systemdelivers an amount of asenapenaine equivalent to the amount of asenapineoriginally provided by the sublingual asenapine therapy.

159. Process of manufacture of a matrix layer for use in a transdermaltherapeutic system according to any one of items 1 to 4 and 20 to 89 and124 to 134 comprising the steps of:

-   -   1) combining at least the components asenapine and polymer, in a        solvent to obtain a coating composition;    -   2) coating the coating composition onto the backing layer or        release liner or any intermediate liner; and    -   3) drying the coated coating composition to form the matrix        layer.        160. Process of manufacture of a matrix layer according to item        159,        wherein in step 1 the asenapine is dissolved to obtain a coating        composition.        161. The process according to item 159 or 160,        wherein preferably the solvent is selected from alcoholic        solvents, in particular methanol, ethanol, isopropanol and        mixtures thereof, and from non-alcoholic solvents, in particular        ethyl acetate, hexane, n-heptane, petroleum ether, toluene, and        mixtures thereof, and more preferably is selected from ethanol        and ethyl acetate.        162. The process according to any one of items 159 to 161,        wherein the polymer is an acrylic polymer and preferably a        copolymer based on vinyl acetate, 2-ethylhexyl-acrylate,        2-hydroxyethyl-acrylate and glycidyl-methacrylate, which is        provided as a solution and preferably as a solution in ethyl        acetate, n-heptane, methanol, ethanol, or any mixtures thereof,        with a solids content of from 30 to 60% by weight.        163. The process according to any one of items 159 to 162,        wherein drying is performed at a temperature of from 50 to        90° C. more preferably from 60 to 80° C.        164. Transdermal therapeutic system for the transdermal        administration of asenapine comprising a self-adhesive layer        structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate; and        -   3. a stabilizer.            165. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of 3% to 9% of the matrix layer composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 90 to 96.5% of            the matrix layer composition; and        -   3. a stabilizer in an amount of from 0.1% to 2% of the            matrix layer composition;            wherein the area weight of the matrix layer ranges from 120            to 170 μm².            166. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate;        -   3. a stabilizer; and        -   4. a polyvinyl pyrrolidone.            167. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of 3% to 9% of the matrix layer composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 80 to 90% of the            matrix layer composition;        -   3. a stabilizer in an amount of from 0.1% to 2% of the            matrix layer composition; and        -   4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of            the matrix layer composition.            wherein the area weight of the matrix layer ranges from 120            to 170 g/m².            168. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of 7% to 13% of the matrix layer composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 75 to 85% of the            matrix layer composition;        -   3. a stabilizer in an amount of from 0.1% to 2% of the            matrix layer composition; and        -   4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of            the matrix layer composition.            wherein the area weight of the matrix layer ranges from 120            to 170 g/m².            169. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of from more than 13% to 20% of the matrix layer            composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 65 to 82% of the            matrix layer composition;        -   3. a stabilizer in an amount of from 0.001% to 2% of the            matrix layer composition; and        -   4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of            the matrix layer composition.            wherein the area weight of the matrix layer ranges from 120            to 230 g/m².            170. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine included in the form of the free base in an            amount of 7% to 20% of the matrix layer composition;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate in an amount of from 75 to 85% of the            matrix layer composition;        -   3. a stabilizer in an amount of from 0.001% to 2% of the            matrix layer composition; and        -   4. a polyvinyl pyrrolidone in an amount of from 5 to 15% of            the matrix layer composition.            wherein the area weight of the matrix layer ranges from more            than 170 to 230 g/m².

The invention relates in particular to the following furtherembodiments:

1. Transdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containing atherapeutically effective amount of asenapine, said self-adhesive layerstructure comprising:

-   -   a) a backing layer;    -   b) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   i) asenapine; and        -   ii) at least one acrylic polymer:            wherein the transdermal therapeutic system has an area of            release of from 5 to 100 cm².            2. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 0.5 to 20 mg/day            over at least 48 hours of administration.            3. Transdermal therapeutic system according to embodiment 2,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 0.5 to 20 mg/day            over at least 72 hours, or over 84 hours of administration,            and/or            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 1.0 to 15            mg/day, or of 2.0 to 10 mg/day over at least 48 hours of            administration.            4. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing asenapine,            wherein the transdermal therapeutic system provides by            transdermal delivery one or more pharmacokinetic            parameter(s) selected from the group consisting of            an asenapine AUC₀₋₄₈ s from 20 to 300 (ng/ml) h or from more            than 300 to 450 (ng/ml) h,            an asenapine AUC₀₋₇₂ from 30 to 400 (ng/ml) h or from more            than 400 to 600 (ng/ml) h,            an asenapine AUC₀₋₈₄ from 35 to 450 (ng/ml) h or from more            than 450 to 700 (ng/ml) h,            an asenapine C_(max) to C₄₈ ratio of less than 2.0,            an asenapine C_(max) to C₇₂ ratio of less than 3.0,            an asenapine C_(max) to C₈₄ ratio of less than 3.5, and            an asenapine C_(max) value of from 0.5 to 10 ng/ml.            5. Transdermal therapeutic system according to any one of            embodiments 2 to 4, comprising a self-adhesive layer            structure containing a therapeutically effective amount of            asenapine, said self-adhesive layer structure comprising:    -   a) a backing layer;    -   b) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   i) asenapine; and        -   ii) a polymer.            6. Transdermal therapeutic system for the transdermal            administration of asenapine comprising a self-adhesive layer            structure containing a therapeutically effective amount of            asenapine, said self-adhesive layer structure comprising:    -   a) a backing layer;    -   b) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   i) asenapine free base; and        -   ii) a polymer;            wherein the asenapine-containing matrix layer has an area            weight that is at least 90 g/m², and wherein the            asenapine-containing matrix layer does not comprise            isopropyl palmitate.            7. Transdermal therapeutic system according to any one of            embodiments 1 to 6,            wherein the transdermal therapeutic system contains at least            0.70 mg/cm², at least 0.80 mg/cm², at least 0.82 mg/cm² or            at least 0.83 mg/cm² asenapine, and/or            wherein the transdermal therapeutic system contains from            0.70 mg/cm² to 4.0 mg/cm², from 0.80 mg/cm² to 3.0 mg/cm²,            from 0.82 mg/cm² to 2.0 mg/cm² or from 0.83 mg/cm² to 1.7            mg/cm² asenapine, and/or            wherein the asenapine-containing matrix layer has an area            weight that ranges from 90 to 230 g/m², from 110 to 210            g/m², or from 120 to 170 g/m².            8. Transdermal therapeutic system according to any one of            embodiments 1 and 5 to 7,            wherein the asenapine-containing matrix layer composition            does not comprise any of polysiloxanes and polyisobutylenes            in an amount of more than 50% of the asenapine-containing            matrix layer composition.            9. Transdermal therapeutic system according to any one of            embodiments 1 and 5 to 8,            wherein the asenapine-containing matrix layer does not            comprise isopropyl myristate in an amount of 5% of the            asenapine-containing matrix layer composition, does not            comprise isopropyl myristate in an amount of 1-10% of the            asenapine-containing matrix layer composition or does not            comprise isopropyl myristate, and/or            wherein the asenapine-containing matrix layer does not            comprise ethyl cellulose in an amount of 10-20% of the            asenapine-containing matrix layer composition or does not            comprise ethyl cellulose, or            wherein the asenapine-containing matrix layer does not            comprise hydrogen chloride.            10. Transdermal therapeutic system according to any one of            embodiments 1 and 5 to 9,            wherein the asenapine in the asenapine-containing matrix            layer composition is included in the form of the free base,            or            wherein the asenapine-containing matrix layer composition is            obtainable by incorporating asenapine free base, and/or            wherein at least 90 mol %, preferably at least 95 mol %,            more preferably at least 98 mol % and most preferably at            least 99 mol % of the asenapine in the asenapine-containing            matrix layer is present in the form of the free base, and/or            wherein the amount of asenapine in the asenapine-containing            matrix layer composition ranges from 2 to 20%, from 3 to 15%            or from 4 to 12% of the asenapine-containing matrix layer            composition.            11. Transdermal therapeutic system according to any one of            embodiments 1 to 3,            wherein the acrylic polymer is selected from a copolymer            based on vinyl acetate, 2-ethylhexyl-acrylate,            2-hydroxyethyl-acrylate and glycidyl-methacrylate, a            copolymer based on methyl acrylate, 2-ethylhexyl acrylate            and t-octyl acrylamide, or a copolymer based on            2-ethylhexyl-acrylate and vinyl acetate.            12. Transdermal therapeutic system according to any one of            embodiments 5 to 10,            wherein the polymer is selected from acrylic polymers, or            from a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate, a copolymer based on methyl acrylate,            2-ethylhexyl acrylate and t-octyl acrylamide, or a copolymer            based on 2-ethylhexyl-acrylate and vinyl acetate.            13. Transdermal therapeutic system according to any one of            embodiments 1 and 5 to 12,            wherein the amount of polymer ranges from 60 to 97%, from 70            to 96% from 75 to 88% or from 91 to 96% of the            asenapine-containing matrix layer composition, or            wherein the total polymer content in the            asenapine-containing matrix layer composition ranges from 75            to 97%, from 80 to 96% or from 85 to 95% of the            asenapine-containing matrix layer composition.            14. Transdermal therapeutic system according to any one of            embodiments 1 and 5 to 13.            wherein the asenapine-containing matrix layer composition            comprises further excipients or additives selected from the            group consisting of cross-linking agents, solubilizers,            fillers, tackifiers, plasticizers, stabilizers, softeners,            substances for skincare, permeation enhancers, pH            regulators, and preservatives.            15. Transdermal therapeutic system according to embodiment            14,            wherein the tackifier is selected from polyvinylpyrrolidone,            triglycerides, dipropylene glycol, resins, resin esters,            terpenes and derivatives thereof, ethylene vinyl acetate            adhesives, dimethylpolysiloxanes and polybutenes, preferably            polyvinylpyrrolidone and more preferably soluble            polyvinylpyrrolidone,            wherein the stabilizer is selected from sodium            metabisulfite, ascorbic acid and ester derivatives thereof,            butylated hydroxytoluene, tocopherol and ester derivatives            thereof such as tocopheryl acetate and tocopheryl linoleate,            as well as a combination of tocopherol and ascorbyl            palmitate, preferably from tocopherol and ester derivatives            thereof and ascorbic acid and ester derivatives thereof, and            is more preferably selected from ascorbyl esters of fatty            acids and tocopherol, and most preferably is ascorbyl            palmitate or α-tocopherol or a combination thereof, or            wherein the permeation enhancer is selected from diethylene            glycol monoethyl ether, diisopropyl adipate, isopropyl            myristate, isopropyl palmitate, lauryl lactate,            dimethylpropylene urea and a mixture of propylene glycol            monoesters and diesters of fatty acids.            16. Transdermal therapeutic system according to any one of            embodiments 1 to 15, providing a skin permeation rate of            asenapine as measured in a Franz diffusion cell with            dermatomed human skin of            0 μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours,            2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24,            3 μg/(cm² h) to 20 μg/(cm² h) from hour 24 to hour 32,            3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour 48,            2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour 72, or            providing a cumulative permeated amount of asenapine as            measured in a Franz diffusion cell with dermatomed human            skin of 0.05 mg/cm² to 1.0 mg/cm², or of 0.1 mg/cm² to 0.7            mg/cm² over a time period of 48 hours, or            providing a cumulative permeated amount of asenapine as            measured in a Franz diffusion cell with dermatomed human            skin of 0.1 mg/cm² to 2.0 mg/cm², or of 0.2 mg/cm² to 1.0            mg/cm² over a time period of 72 hours.            17. Transdermal therapeutic system according to any one of            embodiments 1 to 16 for use in a method of treatment, for            use in a method of treating psychosis, for use in a method            of treating one or more conditions selected from            schizophrenia, bipolar disorder, posttraumatic stress            disorder, major depressive disorder, dementia related            psychosis, agitation and manic disorder, for use in a method            of treating schizophrenia and/or bipolar disorder or for use            in a method of treating bipolar disorder, in particular            acute manic or mixed episodes of bipolar disorder.            18. Transdermal therapeutic system according to embodiment            17 for use in a method of treating a patient,

wherein the transdermal therapeutic system provides a reduction in atleast one asenapine-related side effect relative to an equivalent doseof sublingual asenapine.

19. Transdermal therapeutic system according to embodiment 18 for use ina method of treating a patient, wherein

the patient is a human patient suffering from fatigue, somnolence,dizziness, or any combination thereof, or

the at least one asenapine-related side effect is fatigue, somnolence,dizziness, oral hypoaesthesia, or any combination thereof, or

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness, and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

20. Transdermal therapeutic system according to embodiment 17

for use in a method of reducing, in a patient, at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine.

21. Transdermal therapeutic system according to embodiment 20 for use ina method of reducing, in a patient, at least one asenapine-related sideeffect relative to an equivalent dose of sublingual asenapine, wherein

the patient is a human patient suffering from fatigue, somnolence,dizziness, or any combination thereof, or

the at least one asenapine-related side effect is fatigue, somnolence,dizziness, oral hypoaesthesia, or any combination thereof, or

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

22. A method of treatment, a method of treating psychosis, a method oftreating one or more conditions selected from schizophrenia, bipolardisorder, posttraumatic stress disorder, major depressive disorder,dementia related psychosis, agitation and manic disorder, a method oftreating schizophrenia and/or bipolar disorder, or a method of treatingbipolar disorder and in particular acute manic or mixed episodes ofbipolar disorder,including applying a transdermal therapeutic system according to any oneof embodiments 1 to 16 to the skin of a patient.23. The method of treatment according to embodiment 22wherein the transdermal therapeutic system provides a reduction in atleast one asenapine-related side effect relative to an equivalent doseof sublingual asenapine.24. The method of treatment according to embodiment 23,wherein the patient is a human patient suffering from fatigue,somnolence, dizziness, or any combination thereof.25. The method of treatment according to embodiment 23,wherein the at least one asenapine-related side effect is fatigue,somnolence, dizziness, oral hypoaesthesia, or any combination thereof.26. The method of treatment according to embodiment 23wherein the incidence of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced by atleast about 30%, at least about 40%, at least about 70% or at leastabout 80%, and/or wherein the intensity of the at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine is reduced.27. The method of treatment according to embodiment 26, wherein

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

28. A method of reducing, in a patient, at least one asenapine-relatedside effect relative to an equivalent dose of sublingual asenapine, themethod comprising administering a transdermal therapeutic systemaccording to any one of embodiments 1 to 16.

29. The method according to embodiment 28,

wherein the patient is a human patient suffering from fatigue,somnolence, dizziness, or any combination thereof.

30. The method according to embodiment 28 or 29,

wherein the at least one asenapine-related side effect is fatigue,somnolence, dizziness, oral hypoaesthesia, or any combination thereof.

31. The method according to any one of embodiments 28 to 30

wherein the incidence of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced by atleast about 30%, at least about 40%, at least about 70% or at leastabout 80%, and/or wherein the intensity of the at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine is reduced.32. The method according to embodiment 31, wherein

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%,

33. A method of reducing at least one asenapine-related side effect in apatient being treated with sublingual asenapine therapy, the methodcomprising:

-   -   a) discontinuing sublingual asenapine therapy; and    -   b) administering a transdermal therapeutic system according to        any of embodiments 1 to 16 to the skin of the patient, wherein        the transdermal therapeutic system provides a reduction in at        least one asenapine-related side effect relative to an        equivalent dose of sublingual asenapine.        34. The method of embodiment 33, wherein the transdermal        therapeutic system delivers an amount of asenapenaine equivalent        to the amount of asenapine originally provided by the sublingual        asenapine therapy.        35. Asenapine for use in a method of treating a human patient by        transdermal administration of asenapine for a dosing interval of        at least 48 hours or 2 days.        36. Asenapine for use in a method of treating a human patient        according to embodiment 35,        wherein the dosing interval is at least 72 hours or 3 days, up        to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96        hours or 4 days, or        wherein the dosing interval is 48 hours or 2 days, or 72 hours        or 3 days, or 84 hours or 3.5 days, and/or        providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at        least 48 hours or 2 days of administration, or        providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at        least 72 hours or 3 days of administration, or        providing by transdermal delivery a mean release rate of 0.5 to        20 mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at        least 84 hours or 3.5 days of administration, or        providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300        (ng/ml) h, from more than 300 to 450 (ng/ml) h or from 30 to 200        (ng/ml) h, or        providing by transdermal delivery an AUC₀₋₇₂ from 30 to 400        (ng/ml) h, from more than 400 to 600 (ng/ml) h or from 50 to 300        (ng/ml) h, or        providing by transdermal delivery an AUC₀₋₈₄ from 35 to 450        (ng/ml) h, from more than 450 to 700 (ng/ml) h or from 60 to 350        (ng/ml) h, or        providing by transdermal delivery a C_(max) to C₄₈ ratio of less        than 2.0, less than 1.5 or less than 1.3, or        providing by transdermal delivery a C_(max) to C₇₂ ratio of less        than 3.0, less than 2.5 or less than 2.0, or        providing by transdermal delivery a C_(max) to C₈₄ ratio of less        than 3.5, less than 3.0, less than 2.5 or less than 2.0, or        providing by transdermal delivery a C_(max) value of from 0.5 to        10 ng/ml or from 1 to 8 ng/ml.        37. Asenapine for use in a method of treating a human patient        according to embodiment 35 or 36        wherein at least one asenapine-related side effect relative to        an equivalent dose of sublingual asenapine is reduced.        38. Asenapine for use in a method of treating a human patient        according to embodiment 37, wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, or

the at least one asenapine-related side effect is fatigue, somnolence,dizziness, oral hypoaesthesia, or any combination thereof, or

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

39. Transdermal therapeutic system for the transdermal administration ofasenapine for use in a method of treating a human patient for a dosinginterval of at least 48 hours or 2 days.

40. Transdermal therapeutic system for use in a method of treating ahuman patient according to embodiment 39,

for a dosing interval of at least 72 hours or 3 days, up to 168 hours or7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days, or

wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3days, or 84 hours or 3.5 days, and/or

providing by transdermal delivery a mean release rate of 0.5 to 20mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 48 hoursof administration, or

providing by transdermal delivery a mean release rate of 0.5 to 20mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 72 hoursof administration, or

providing by transdermal delivery a mean release rate of 0.5 to 20mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 84 hoursof administration, or

providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300 (ng/ml) h,from more than 300 to 450 (ng/ml) h or from 30 to 200 (ng/ml) h, or

providing by transdermal delivery an AUC₀₋₇₂ from 30 to 400 (ng/ml) h,from more than 400 to 600 (ng/ml) h or from 50 to 300 (ng/ml) h, or

providing by transdermal delivery an AUC₀₋₈₄ from 35 to 450 (ng/ml) h,from more than 450 to 700 (ng/ml) h or from 60 to 350 (ng/ml) h, or

providing by transdermal delivery a C_(max) to C₄₈ ratio of less than2.0, less than 1.5 or less than 1.3, or

providing by transdermal delivery a C_(max) to C₇₂ ratio of less than3.0, less than 2.5 or less than 2.0, or

providing by transdermal delivery a C_(max) to C₈₄ ratio of less than3.5, less than 3.0, less than 2.5 or less than 2.0, or

providing by transdermal delivery a C_(max) value of from 0.5 to 10ng/ml or from 1 to 8 ng/ml.

41. Transdermal therapeutic system according to embodiment 39 or 40 foruse in a method of treating a patient,

wherein the transdermal therapeutic system provides a reduction in atleast one asenapine-related side effect relative to an equivalent doseof sublingual asenapine.

42. Transdermal therapeutic system according to embodiment 41 for use ina method of treating a patient, wherein

the patient is a human patient suffering from fatigue, somnolence,dizziness, or any combination thereof, or

the at least one asenapine-related side effect is fatigue, somnolence,dizziness, oral hypoaesthesia, or any combination thereof, or

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

43. A method of treating a human patient by transdermal administrationof asenapine for a dosing interval of at least 48 hours or 2 days.

44. The method of treating a human patient by transdermal administrationof asenapine according to embodiment 43, for a dosing interval of atleast 72 hours or 3 days, up to 168 hours or 7 days, up to 120 hours or5 days, or up to 96 hours or 4 days, or

wherein the dosing interval is 48 hours or 2 days, or 72 hours or 3days, or 84 hours or 3.5 days, and/or

providing by transdermal delivery a mean release rate of 0.5 to 20mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 48 hoursof administration, or

providing by transdermal delivery a mean release rate of 0.5 to 20mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 72 hoursof administration, or

providing by transdermal delivery a mean release rate of 0.5 to 20mg/day, 1.0 to 15 mg/day, or of 2.0 to 10 mg/day over at least 84 hoursof administration, or

providing by transdermal delivery an AUC₀₋₄₈ from 20 to 300 (ng/ml) h,from more than 300 to 450 (ng/ml) h or from 30 to 200 (ng/ml) h, or

providing by transdermal delivery an AUC₀₋₇₂ from 30 to 400 (ng/ml) h,from more than 400 to 600 (ng/ml) h or from 50 to 300 (ng/ml) h, or

providing by transdermal delivery an AUC₀₋₈₄ from 35 to 450 (ng/ml) h,from more than 450 to 700 (ng/ml) h or from 60 to 350 (ng/ml) h, or

providing by transdermal delivery a C_(max) to C₄₈ ratio of less than2.0, less than 1.5 or less than 1.3, or

providing by transdermal delivery a C_(max) to C₇₂ ratio of less than3.0, less than 2.5 or less than 2.0, or

providing by transdermal delivery a C_(max) to C₈₄ ratio of less than3.5, less than 3.0, less than 2.5 or less than 2.0, or

providing by transdermal delivery a C_(max) value of from 0.5 to 10ng/ml or from 1 to 8 ng/ml.

45. The method of treating a human patient according to embodiment 43 or44

wherein the transdermal administration of asenapine provides a reductionin at least one asenapine-related side effect relative to an equivalentdose of sublingual asenapine.

46. The method of treating a human patient according to embodiment 45,

wherein the human patient is suffering from fatigue, somnolence,dizziness, or any combination thereof.

47. The method of treating a human patient according to embodiment 45 or46,

wherein the at least one asenapine-related side effect is fatigue,somnolence, dizziness, oral hypoaesthesia, or any combination thereof.

48. The method of treating a human patient according to any one ofembodiments 45 to 47 wherein the incidence of the at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine is reduced by at least about 30%, at least about40%, at least about 70% at least about 80%, and/or wherein the intensityof the at least one asenapine-related side effect relative to anequivalent dose of sublingual asenapine is reduced.

49. The method of treating a human patient according to embodiment 48,wherein

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% at least about 40% and/or theintensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

50. Transdermal therapeutic system for the transdermal administration ofasenapine for use in a method of treating a human patient, wherein

the transdermal therapeutic system provides a reduction in at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine, and wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

51. Transdermal therapeutic system according to embodiment 50 for use ina method of treating a human patient, wherein

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

52. A method of treating a human patient by transdermal administrationof asenapine wherein at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced, and wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

53. The method of treating a human patient according to embodiment 52,wherein

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

54. A method of reducing, in a human patient, at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine, the method comprising transdermal administrationof asenapine, wherein

the human patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

55. The method of treating a human patient according to embodiment 54,wherein

the incidence of the at least one asenapine-related side effect relativeto an equivalent dose of sublingual asenapine is reduced by at leastabout 30%, at least about 40%, at least about 70% or at least about 80%,and/or the intensity of the at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine is reduced, or

the at least one asenapine-related side effect is fatigue and theincidence of fatigue relative to an equivalent dose of sublingualasenapine is reduced by at least about 30% or at least about 40% and/orthe intensity of fatigue relative to an equivalent dose of sublingualasenapine is reduced, or

the at least one asenapine-related side effect is dizziness and theincidence of dizziness relative to an equivalent dose of sublingualasenapine is reduced by at least about 30%, at least about 40%, at leastabout 70% or at least about 80%.

56. A method of reducing at least one asenapine-related side effect in apatient being treated with sublingual asenapine therapy, the methodcomprising:

a) discontinuing sublingual asenapine therapy; and

b) transdermal administration of asenapine,

wherein the patient is suffering from fatigue, somnolence, dizziness, orany combination thereof, and/or the at least one asenapine-related sideeffect is fatigue, somnolence, dizziness, oral hypoaesthesia, or anycombination thereof.

57. Process of manufacture of a matrix layer for use in a transdermaltherapeutic system according to any one of embodiments 1 and 5 to 16comprising the steps of:

-   -   1) combining at least the components asenapine and polymer, in a        solvent to obtain a coating composition;    -   2) coating the coating composition onto the backing layer or        release liner or any intermediate liner; and    -   3) drying the coated coating composition to form the matrix        layer.        58. Transdermal therapeutic system according to any one of        embodiments 1, 5-17, and 22 wherein the matrix layer composition        comprises:    -   i) 3 to 9% by weight of asenapine free base;    -   ii) 80 to 90% by weight of a copolymer based on vinyl acetate,        2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate, and        glycidyl-methacrylate;    -   iii) 0.1 to 2% by weight of tocopherol; and    -   iv) 5 to 15% by weight of polyvinylpyrrolidone.        59. Transdermal therapeutic system according to any one of        embodiments 1, 5-17, 22, and 58, wherein the matrix layer        composition comprises:

i) about 6% by weight of asenapine free base;

ii) about 83.5% by weight of an acrylic polymer;

iii) about 0.5% by weight of tocopherol; and

iv) about 10% by weight of polyvinylpyrrolidone.

60. Transdermal therapeutic system according to any one of embodiments1, 5-17, and 22 wherein the matrix layer composition comprises:

-   -   i) 7 to 13% by weight of asenapine free base;    -   ii) 75 to 85% by weight of a copolymer based on vinyl acetate,        2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate, and        glycidyl-methacrylate;    -   iii) 0.1 to 2% by weight of tocopherol; and    -   iv) 5 to 15% by weight of polyvinylpyrrolidone.        61. Transdermal therapeutic system according to any one of        embodiments 1, 5-17, 22, and 60, wherein the matrix layer        composition comprises:

i) about 10% by weight of asenapine free base;

ii) 77 to 82% by weight of an acrylic polymer;

iii) about 0.5% by weight of tocopherol; and

iv) about 10% by weight of polyvinylpyrrolidone.

62. A method of treating schizophrenia in a patient in need thereof, themethod comprising administering to the patient a transdermal therapeuticsystem comprising a self-adhesive layer structure, the self-adhesivelayer structure comprising:

-   -   a) a backing layer;    -   b) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   i) a therapeutically effective amount of asenapine; and        -   ii) an acrylic polymer.            63. The method according to embodiment 62, wherein the            transdermal therapeutic system provides by transdermal            delivery a mean release rate of 0.5 to 20 mg/day over at            least 48 hours of administration.            64. The method according to any of embodiments 62 or 63,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 0.5 to 20 mg/day            over at least 84 hours of administration.            65. The method according to any of embodiments 62-64,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 1.0 to 15 mg/day            over at least 48 hours of administration.            66. The method according to any of embodiments 62-65,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 2.0 to 10 mg-day            over at least 48 hours of administration.            67. The method according to any one of embodiments 62-66,            wherein the transdermal therapeutic system provides by            transdermal delivery one or more pharmacokinetic            parameter(s) selected from the group consisting of            an asenapine AUC₀₋₄₈ from 20 to 300 (ng/ml) h, or from more            than 300 to 450 (ng/ml) h,            an asenapine AUC₀₋₇₂ from 30 to 400 (ng/ml) h or from more            than 400 to 600 (ng/ml) h.            an asenapine AUC₀₋₈₄ from 35 to 450 (ng/ml) h or from more            than 450 to 700 (ng/ml) h,            an asenapine C_(max) to C₄₈ ratio of less than 2.0,            an asenapine C_(max) to C₇₂ ratio of less than 3.0,            an asenapine C_(max) to C₈₄ ratio of less than 3.5, and            an asenapine C_(max) value of from 0.5 to 10 ng/ml.            68. The method according to any one of embodiments 62-67,            wherein the asenapine-containing matrix layer has an area            weight that is at least 90 g/m².            69. The method according to any one of embodiments 62-68,            wherein the transdermal therapeutic system contains at least            0.70 mg/cm² of asenapine.            70. The method according to any one of embodiments 62-69,            wherein the asenapine-containing matrix layer has an area            weight that ranges from 90 to 230 g/m².            71. The method according any one of embodiments 62-70,            wherein the asenapine in the asenapine-containing matrix            layer composition is asenapine free base.            72. The method according any one of embodiment 62-71,            wherein at least 90 mol % of the asenapine in the            asenapine-containing matrix layer is asenapine free base.            73. The method according to any one of embodiments 62-72,            wherein the matrix layer composition comprises further            excipients or additives selected from the group consisting            of cross-linking agents, solubilizers, fillers, tackifiers,            plasticizers, stabilizers, softeners, substances for            skincare, permeation enhancers, pH regulators, and            preservatives, wherein

the tackifier is selected from polyvinylpyrrolidone, triglycerides,dipropylene glycol, resins, resin esters, terpenes and derivativesthereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes andpolybutenes;

the stabilizer is selected from tocopherol and ester derivatives thereofand ascorbic acid and ester derivatives thereof; and

the permeation enhancer is selected from diethylene glycol monoethylether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate,lauryl lactate, dimethylpropylene urea and a mixture of propylene glycolmonoesters and diesters of fatty acids.

74. The method according to any one of embodiments 62-73, wherein thetransdermal therapeutic system provides a skin permeation rate ofasenapine as measured in a Franz diffusion cell with dermatomed humanskin of

0 μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours,

2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24.

3 μg/(cm² h) to 20 μg/(cm² h) from hour 24 to hour 32,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour 48, or

2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour 72.

75. The method according to any one of embodiments 62-74, wherein thetransdermal therapeutic system is administered at a dosing interval ofat least 48 hours or 2 days.

76. The method according to any one of embodiments 62-75, wherein thetransdermal therapeutic system provides by transdermal delivery a meanrelease rate of 0.5 to 20 mg/day over at least 48 hours or 2 days ofadministration.

77. The method according to any one of embodiments 62-76, wherein thetransdermal therapeutic system provides by transdermal delivery anAUC₀₋₄₈ from 20 to 300 (ng/ml) h or from more than 300 to 450 (ng/ml) h.

78. The method according to any one of embodiments 62-77, wherein thetransdermal therapeutic system provides by transdermal delivery aC_(max) to C₄n ratio of less than 2.0.

79. The method according to any one of embodiments 62-78, wherein thematrix layer composition comprises:

i) 4 to 12% by weight of asenapine free base:

ii) 75 to 88% by weight of an acrylic polymer;

iii) 0.01 to 1.0% by weight of tocopherol; and

iv) 7 to 13% by weight of polyvinylpyrrolidone.

80. The method according to any one of embodiments 62-79, wherein thematrix layer composition comprises:

i) about 6% by weight of asenapine free base;

ii) 81 to 85% by weight of an acrylic polymer;

iii) about 0.5% by weight of tocopherol; and

iv) about 10% by weight of polyvinylpyrrolidone.

81. The method according to any one of embodiments 62-80, wherein thematrix layer composition comprises:

i) about 10% by weight of asenapine:

ii) 77 to 82% by weight of an acrylic polymer;

iii) about 0.5% by weight of tocopherol; and

iv) about 10% by weight of polyvinylpyrrolidone.

82. A method of treating bipolar disorder in a patient in need thereof,the method comprising administering to the patient a transdermaltherapeutic system comprising a self-adhesive layer structure, saidself-adhesive layer structure comprising:

-   -   a) a backing layer; and    -   b) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   i) a therapeutically effective amount of asenapine; and        -   ii) an acrylic polymer.            83. The method according to embodiment 82, wherein the            bipolar disorder is acute manic bipolar disorder.            84. The method according to embodiment 82, wherein the            bipolar disorder is mixed episodes of bipolar disorder.            85. The method according to any of embodiments 82-84,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 0.5 to 20 mg/day            over at least 48 hours of administration.            86. The method according to any of embodiments 82-85,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 0.5 to 20 mg/day            over at least 84 hours of administration.            87. The method according to any of embodiments 82-86,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 1.0 to 15 mg/day            over at least 48 hours of administration.            88. The method according to any of embodiments 82-87,            wherein the transdermal therapeutic system provides by            transdermal delivery a mean release rate of 2.0 to 10 mg/day            over at least 48 hours of administration.            89. The method according to any one of embodiments 82-88,            wherein the transdermal therapeutic system provides by            transdermal delivery one or more pharmacokinetic            parameter(s) selected from the group consisting of            an asenapine AUC₀₋₄₈ from 20 to 300 (ng/ml) h, or from more            than 300 to 450 (ng/ml) h,            an asenapine AUC₀₋₇₂ from 30 to 400 (ng/ml) h, or from more            than 400 to 600 (ng/ml) h,            an asenapine AUC₀₋₈₄ from 35 to 450 (ng/ml) h, or from more            than 450 to 700 (ng/ml) h,            an asenapine C_(max) to C₄₈ ratio of less than 2.0,            an asenapine C_(max) to C₇₂ ratio of less than 3.0,            an asenapine C_(max) to C₈₄ ratio of less than 3.5, and            an asenapine C_(max) value of from 0.5 to 10 ng/ml.            90. The method according to any one of embodiments 82-89,            wherein the asenapine-containing matrix layer has an area            weight that is at least 90 g/m².            91. The method according to any one of embodiments 82-90,            wherein the transdermal therapeutic system contains at least            0.70 mg/cm² of asenapine.            92. The method according to any one of embodiments 82-91,            wherein the asepnapine-containing matrix layer has an area            weight that ranges from 90 to 230 g/m².            93. The method according any one of embodiments 82-92,            wherein the asenapine in the asenapine-containing matrix            layer composition is asenapine free base.            94. The method according any one of embodiment 82-93,            wherein at least 90 mol % of the asenapine in the            asenapine-containing matrix layer is asenapine free base.            95. The method according to any one of embodiments 82-94,            wherein the matrix layer composition comprises further            excipients or additives selected from the group consisting            of cross-linking agents, solubilizers, fillers, tackifiers,            plasticizers, stabilizers, softeners, substances for            skincare, permeation enhancers, pH regulators, and            preservatives, wherein

the tackifier is selected from polyvinylpyrrolidone, triglycerides,dipropylene glycol, resins, resin esters, terpenes and derivativesthereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes andpolybutenes;

the stabilizer is selected from tocopherol and ester derivatives thereofand ascorbic acid and ester derivatives thereof; and

the permeation enhancer is selected from diethylene glycol monoethylether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate,lauryl lactate, dimethylpropylene urea, and a mixture of propyleneglycol monoesters and diesters of fatty acids.

96. The method according to any one of embodiments 82-95, wherein thetransdermal therapeutic system provides a skin permeation rate ofasenapine as measured in a Franz diffusion cell with dermatomed humanskin of

0 μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours,

2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 24 to hour 32,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour 48, or

2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour 72.

97. The method according to any one of embodiments 82-96, wherein thetransdermal therapeutic system provides by transdermal delivery a meanrelease rate of 0.5 to 20 mg/day over at least 48 hours ofadministration.

98. The method according to any one of embodiments 82-97, wherein thetransdermal therapeutic system provides by transdermal delivery a meanrelease rate of 0.5 to 20 mg/day over at least 84 hours ofadministration.

99. The method according to any one of embodiments 82-98, wherein thetransdermal therapeutic system provides by transdermal delivery a meanrelease rate of 1.0 to 15 mg/day over at least 48 hours ofadministration.

100. The method according to any one of embodiments 82-99, wherein thetransdermal therapeutic system provides by transdermal delivery a meanrelease rate of 2.0 to 10 mg/day over at least 48 hours ofadministration.

101. The method according to any one of embodiments 82-100, wherein thematrix layer composition comprises:

i) 4 to 12% by weight of asenapine free base;

ii) 75 to 88% by weight of an acrylic polymer;

iii) 0.01 to 1.0% by weight of tocopherol; and

iv) 7 to 13% by weight of polyvinylpyrrolidone.

102. The method according to any one of embodiments 82-101, wherein thematrix layer composition comprises:

i) about 6% by weight of asenapine free base;

ii) 81 to 85% by weight of an acrylic polymer:

iii) about 0.5% by weight of tocopherol; and

iv) about 10% by weight of polyvinylpyrrolidone.

103. The method according to any one of embodiments 82-102, wherein thematrix layer composition comprises:

i) about 10% by weight of asenapine free base;

ii) 77 to 82% by weight of an acrylic polymer:

iii) about 0.5% by weight of tocopherol; and

iv) about 10% by weight of polyvinylpyrrolidone.

104. A method of treating schizophrenia or bipolar disorder in a subjectin need thereof, the method comprising transdermally administering atherapeutically effective amount of asenapine to the subject, whereinthe asenapine is contained in a transdermal therapeutic system for thetransdermal administration of asenapine, and wherein the transdermaltherapeutic system is in contact with at least one body surface on thesubject for about 84 hours.105. The method according to embodiment 104, wherein the transdermaltherapeutic system provides by transdermal delivery one or morepharmacokinetic parameter(s) selected from the group consisting ofan asenapine AUC₀₋₄₈ from 20 to 300 (ng/ml) h, or from more than 300 to450 (ng/ml) h,an asenapine AUC₀₋₇₂ from 30 to 400 (ng/ml) h, or from more than 400 to600 (ng/ml) h,an asenapine AUC₀₋₈₄ from 35 to 450 (ng/ml) h, or from more than 450 to700 (ng/ml) h.an asenapine C_(max) to C₄₈ ratio of less than 2.0,an asenapine C_(max) to C₇₂ ratio of less than 3.0,an asenapine C_(max) to C₈₄ ratio of less than 3.5, andan asenapine C_(max) value of from 0.5 to 10 ng/ml.106. The method according to any of embodiments 104 or 105, wherein thetransdermal therapeutic system provides by transdermal delivery a meanrelease rate of 0.5 to 20 mg/day.107. The method according to any of embodiments 104-106, wherein thetransdermal therapeutic system comprises a self-adhesive layerstructure, said self-adhesive layer structure comprising:

-   -   a) a backing layer; and    -   b) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   i) a therapeutically effective amount of asenapine; and        -   ii) an acrylic polymer.            108. The method of embodiment 107, wherein the asenapine in            the asenapine-containing matrix layer is asenapine free            base.            109. The method according to embodiment 107 or 108, wherein            at least 90 mol % of the asenapine in the            asenapine-containing matrix layer is asenapine free base.            110. The method according to any one of embodiments 107-109,            wherein the matrix layer composition comprises further            excipients or additives selected from the group consisting            of cross-linking agents, solubilizers, fillers, tackifiers,            plasticizers, stabilizers, softeners, substances for            skincare, permeation enhancers, pH regulators, and            preservatives.            111. The method according to any one of embodiments 107-110,            wherein the transdermal therapeutic system provides a skin            permeation rate of asenapine as measured in a Franz            diffusion cell with dermatomed human skin of

0 μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours,

2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 24 to hour 32,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour 48, or

2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour 72.

112. The method according to any one of embodiments 107-111, wherein thematrix layer composition comprises:

i) 4 to 12% by weight of asenapine free base;

ii) 75 to 88% by weight of an acrylic polymer,

iii) 0.01 to 1.0% by weight of tocopherol; and

iv) 7 to 13% by weight of polyvinylpyrrolidone.

113. The method according to any one of embodiments 107-112, wherein thematrix layer composition comprises:

i) about 6% by weight of asenapine free base;

ii) 81 to 85% by weight of an acrylic polymer;

iii) about 0.5% by weight of tocopherol; and

iv) about 10% by weight of polyvinylpyrrolidone.

114. The method according to any one of embodiments 107-113, wherein thematrix layer composition comprises:

i) about 10% by weight of asenapine free base;

ii) 77 to 82% by weight of an acrylic polymer;

iii) about 0.5% by weight of tocopherol; and

iv) about 10% by weight of polyvinylpyrrolidone.

What is claimed is:
 1. A method of treating schizophrenia, the methodcomprising administering to a subject in need thereof, a transdermaltherapeutic system comprising: a) a polyester backing layer; and b) anasenapine-containing matrix layer comprising asenapine and a polymer;wherein the transdermal therapeutic system has an area of releaseranging from 10 to 80 cm²; the amount of asenapine in theasenapine-containing matrix layer ranges from 2 to about 20% by weight;the asenapine-containing matrix layer has an area weight ranging from 90to 230 g/m²; and wherein the polymer comprises astyrene-isoprene-styrene block copolymer; further wherein thetransdermal therapeutic system provides: a mean transdermal asenapinerelease rate of 2.0 to 10 mg/day; and an asenapine C_(max) value of from0.5 to 10 ng/ml following administration of the transdermal system tothe skin of the subject in need thereof.
 2. The method of claim 1,wherein the asenapine in the asenapine-containing matrix layer isasenapine free base.
 3. The method of claim 1, wherein the asenapine inthe asenapine-containing matrix layer is an asenapine salt.
 4. Themethod of claim 1, wherein the asenapine in the asenapine-containingmatrix layer is a mixture of an asenapine salt and asenapine free base.5. The method of claim 4, wherein the asenapine salt is asenapinemaleate.
 6. The method of claim 1, wherein the transdermal therapeuticsystem provides an asenapine C_(max) value of from 1 to 8 ng/ml or from1.5 to 5 ng/ml following administration of the transdermal system toskin of the subject in need thereof.
 7. The method of claim 1, whereinthe transdermal therapeutic system further provides an asenapine AUC₀₋₂₄ranging from about 20 [(ng/ml)h] to about 78 [(ng/ml)h] followingadministration of the system to skin of the subject in need thereof. 8.The method of claim 7, wherein the transdermal therapeutic systemfurther provides a des-methyl-asenapine AUC₀₋₂₄ ranging from about 0.4[(ng/ml)h] to about 6 [(ng/ml)h] following administration of the systemto skin of the subject in need thereof.
 9. The method of claim 1,wherein the transdermal therapeutic system further provides an AUC₀₋₂₄within 10% to 1000% of the steady state AUC₀₋₂₄ obtained uponadministration of twice daily 5 mg sublingual asenapine followingadministration of the system to skin of the subject in need thereof. 10.The method of claim 1, wherein the polymer further comprises apolyisobutylene adhesive.
 11. The method of claim 10, wherein thepolymer comprises a polyisobutylene adhesive in an amount not exceedingmore than 50% by weight of the matrix layer.
 12. The method of claim 1,wherein the transdermal therapeutic system contains from about 5 to 100mg asenapine.
 13. The method of claim 1, wherein the amount of asenapinein the asenapine-containing matrix layer ranges from 2 to 4% by weight.14. The method of claim 1, wherein the matrix layer further comprisesone or more additives selected from the group consisting of a resin,butylated hydroxytoluene, and isopropyl palmitate.
 15. The method ofclaim 1, wherein the transdermal therapeutic system provides a skinpermeation rate of asenapine as measured in a Franz diffusion cell withdermatomed human skin of 0 μg/(cm² h) to 10 μg/(cm² h) in the first 8hours, 2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24, 3 μg/(cm²h) to 20 μg/(cm² h) from hour 24 to hour 32, 3 μg/(cm² h) to 20 μg/(cm²h) from hour 32 to hour 48, 2 μg/(cm² h) to 15 μg/(cm² h) from hour 48to hour
 72. 16. The method of claim 1, wherein the transdermal system isexchanged once per day.
 17. The method of claim 1, wherein fluctuationin asenapine blood plasma concentration is reduced when compared tosublingual administration at steady state.
 18. The method of claim 1,wherein administering the transdermal therapeutic system to the subjectin need thereof reduces at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine.
 19. The methodof claim 18, wherein the at least one asenapine-related side effect isselected from the group consisting of fatigue, somnolence, dizziness,oral hypoaesthesia, and a combination thereof.
 20. The method of claim1, wherein the subject is selected from the group consisting of anadult, an adolescent and a pediatric subject.
 21. The method of claim 1,wherein administering the transdermal system to a subject in needthereof comprises applying the transdermal system to the subject's arm,chest, or back.
 22. The method of claim 1, wherein the C_(max) isachieved at a t_(max) ranging from about 16 to about 24 hours.
 23. Amethod of treating schizophrenia in an adult subject, the methodcomprising administering to an adult subject in need thereof, atransdermal therapeutic system comprising: a. a polyester backing layer;and b. an asenapine-containing matrix layer comprising asenapine, apolyisobutylene adhesive in an amount not exceeding more than 50% byweight of the matrix layer, and a styrene-isoprene-styrene copolymer;wherein the transdermal therapeutic system has an area of releaseranging from 10 to 80 cm²; the amount of asenapine in theasenapine-containing matrix layer ranges from 2 to 20 by weight; and theasenapine-containing matrix layer has an area weight ranging from 90 to230 g/m²; further wherein the transdermal therapeutic system provides: amean transdermal asenapine release rate of 2.0 to 10 mg/day; and anasenapine C_(max) value of from 0.5 to 10 ng/ml following administrationof the transdermal system to skin of the subject in need thereof. 24.The method of claim 23, wherein the asenapine in theasenapine-containing matrix layer is selected from asenapine free base,an asenapine salt, and a mixture of an asenapine salt and asenapine freebase.
 25. The method of claim 24, wherein the asenapine salt isasenapine maleate.
 26. The method of claim 23, wherein the transdermaltherapeutic system provides an asenapine C_(max) value of from 1 to 8ng/ml or from 1.5 to 5 ng/ml following administration of the transdermalsystem to skin of the subject in need thereof.
 27. The method of claim23, wherein the C_(max) is achieved at a t_(max) ranging from about 16to about 24 hours.
 28. The method of claim 1, wherein the amount ofasenapine in the asenapine-containing matrix layer ranges from 3 to 15%by weight.
 29. The method of claim 23, wherein the amount of asenapinein the asenapine-containing matrix layer ranges from 3 to 15% by weight.